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Issue 10 | January - March 2018

UNLOCKING
GRIDLOCK
Clearing the road
for driverless cars

METFORMIN ON THE ALLERGY EPIDEMIC
REPURPOSED RECORD GRIPS ASIA
Diabetes stalwart could be Power-assisted Singapore’s hay-fever levels
adapted for cancer treatment crime fighting not to be sniffed at
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
articles. All articles are first published engineering, and spurs growth in Singapore’s key economic
online on the A*STAR Research website
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use only. Modification or commercial use
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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

EDITORIAL
3 Notes from the editors

F E AT U R E S &
I N N O VAT I O N S
4 Hay fever
8 Green lights all the way

RESEARCH
HIGHLIGHTS
13 A better angle

4 F E AT U R E S &
I N N O VAT I O N S
on microscopic devices
14 Taking a stab at microbes
15 Shedding ‘light’
on antibody design
16 A new weapon against
the Zika virus
17 Computing the ebb and flow
18 Using a mouse to make an ‘iMac’
19 Of mice and men
20 Gut bacteria implicated
in liver inflammation
17 18 21 A catalyst for change
in chemical etching
22 Keeping stem cells naïve
24 Bridging the security divide
for chat applications
25 What a hungry fly can tell us
about obesity
26 A smoother finish
allows fluids to flow
27 Hepatitis B exploits

22 the liver's weaknesses
28 Clinging on to memory

www.research.a-star.edu.sg  A*STAR RESEARCH 1
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

RESEARCH
HIGHLIGHTS
29 Classify and conquer
30 Frequency fingerprints increase
crime-fighting power
32 Diverting distraction
33 Getting to the root of hair loss
34 A simpler path
35 Fetal immune system
developed, but tolerant
36 Mapping RNA editing
37 Escaping silicon
38 More evidence for metformin
40 Hormone discovery opens path
for new pre-eclampsia treatment
41 Let liquid fingers point the way
42 All in a molecule of water
for effective cancer therapy

30 43 Faster data transfer
through plasmons
44 Eyes on the road
for retina mapping
45 Picking winners from millions
of possibilities
46 Healing damaged hearts
47 Making light work
42 of nanpositioning
48 An all-in-one catalyst
49 Flat-packed optical components
50 Putting the ‘bones’ in order
51 Floating nanostructures
for better color

NEXT ISSUE
35 46 52 A sneak peek of Issue 11
2 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

NOTES
FROM THE EDITORS
Editorial board member, Arseniy Kuznetsov,
introduces the latest issue of A*STAR Research

W
elcome to the second called metasurfaces, that could eventu- discoveries that have important implica-
edition of A*STAR ally replace bulky glass lenses, enabling tions for fetal and maternal health: the
Research for 2018, where higher imaging resolution and providing discovery of a hormone that could treat
we showcase some of the an excellent compact and lightweight a dangerous complication of pregnan-
latest innovations and research from solution for mobile device cameras cy (page 40), and the unravelling of
A*STAR. and head-mounted displays (page 49). mysteries surrounding the fetal immune
More than half of the world’s Another example is a new ultra-high res- system (page 35).
population lives in urban areas — a olution printing method based on reso- We also have a full-length feature
proportion that is expected to grow to nant silicon nanostructures, which can that examines a health issue that affects
two-thirds by 2050. With overcrowding now achieve a spread of colours beyond many of us — allergies, and a common
comes traffic jams and gridlocks, but standard RGB (page 51). Additionally, culprit that lurks in our homes (page 4).
smarter transport systems that are being a team of A*STAR and NUS researchers Another inflammation-related article
developed and tested in Singapore could have developed transducers that could reveals a surprising role for gut bacteria
overcome these problems (read more in transfer data directly from electrical in chronic viral hepatitis, which may
our cover story on page 8). signals to plasmonic circuits and back, influence future treatments (page 20).
Several exciting inventions have also avoiding speed reductions from elec- As usual, there are many more
emerged from the field of nanophotonics tro-optical components (page 43). interesting stories in the rest of the
and plasmonics. These include arrays Major advances have been made magazine, and I hope you will enjoy
of resonant dielectric nanostructures, in medicine as well — including two reading them.

Issue 10 | January - March 2018
A*STAR RESEARCH

UNLOCKING
GRIDLOCK
Clearing the road
for driverless cars
© Colin Anderson/Photographer’s Choice RF/Getty

ISSUE 10 January - March 2018

METFORMIN ON THE ALLERGY EPIDEMIC
REPURPOSED RECORD GRIPS ASIA
Diabetes stalwart could be Power-assisted Singapore’s hay-fever levels
adapted for cancer treatment crime fighting not to be sniffed at

COVER IMAGE
Singapore is an ideal test
bed for intelligent traffic
innovation. [page 8]
© RETOKA

www.research.a-star.edu.sg A*STAR RESEARCH 3
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

HAY
With dust mites likely causing
allergic rhinitis symptoms in
an enormous 40 per cent of
Singapore’s population, research in
the city state is yielding some very
interesting insights into the role of

FEVER
climate, genetics and childhood

© K.H. Kjeldsen/Science Photo Library

People living in countries
within the tropical belt
(Singapore, Malaysia,
Indonesia and others) with
comparable climates showed
similar evidence of exposure
to two species of dust
mite, Dermatophagoides
pteronyssinus (right) and
Blomia tropicalis.

4 A*STAR RESEARCH  Issue 10 | January – March 2018
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F
irst, the bad news: on busy cities in tropical
There’s no simple cure climates — environments in
for allergies… which dust mites thrive.
at least for now. In fact, allergic rhinitis
One of the most could be having a hefty effect
widespread, allergic rhinitis on productivity worldwide.
(or hay fever) affects as much Roughly eight per cent of adults
as five per cent of the world’s experience allergic rhinitis in
population. The hallmarks the United States, while other
are sniffling, itching and national surveys have estimated
sneezing, and it strikes prevalence rates of about
indiscriminately, regardless of six per cent in France and 29
age or ethnic background. per cent in the United Kingdom.
No-one knows why some More than just an irritation,
people develop this common common symptoms of
allergy and not others, but allergic rhinitis are also loss
An A*STAR study has suggested that wheezing and eczema in infancy are correlated
scientists in Singapore have of sleep, irritability and with having an increased risk of sensitization to airborne allergens, including allergic
recently found some interesting fatigue — all of which have rhinitis (hay fever), later in childhood.
clues in cell responses and an effect on performance at
childhood experiences. work and school.
Allergies are essentially
glitches of the immune system. EIGHT-LEGGED CULPRIT
The human body responds to
some usually harmless material
A survey of 8,000 adults in
Singapore published in Allergy
75% 40%
of Singaporeans
of Singaporeans
have allergen
by activating an immune in 2014 found an astonishing antibodies
show allergy
symptoms
response that releases a number 40 per cent of those surveyed
of substances. The main culprit, reported symptoms of
histamine, sparks inflammation allergic rhinitis.
and is responsible for the most In fact, by testing the blood
irritating symptoms, including of nearly 600 people, the team tropicalis. The unpleasant truth with other colleagues at
itching and swelling. found a staggering 80 per cent is that people are not allergic to SIgN and collaborators at
In spring, people often suffer of Singaporeans had antibodies, the mites themselves, but their the National University of
© Getty Images/Clover No.7 Photography

from what is known as seasonal called Immunoglobulin E (IgE), fecal matter. Singapore (NUS).
or intermittent allergic rhinitis that are specific to house “To verify our findings, “Astonishingly, we found
— triggered by pollen from trees dust mites. we looked at a much larger the figure was similarly high:
and grasses, as well as fungal Two species of dust sample size of more than 75 per cent of this larger
spores. Less seasonal is the mite that are often found in 7,000 volunteers,” says Anand group had antibodies against
allergic rhinitis triggered by dust mattresses, bed linen, carpets Andiappan, a senior research house dust mites.” That
mites, animal dander (such as and upholstered furniture were scientist at A*STAR’s Singapore means that three-quarters of
pet fur), mold and cockroaches. implicated: Dermatophagoides Immunology Network (SIgN), Singaporeans potentially have
The latter can be a huge burden pteronyssinus and Blomia who worked on the study a dust mite allergy.

www.research.a-star.edu.sg A*STAR RESEARCH 5
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IT’S NOT ABOUT ETHNICITY This suggested that climate is a summer, they usually die off could be involved, such as pollen,
As part of the 2014 study, the significant factor in determining during the drier winter months. fungi and animal dander. “The
researchers looked closely at exposure levels and allergic To Olaf Rötzschke, a advantage here in Singapore
the ethnic Chinese portion of response: People from countries principal investigator at SIgN is that we have a perfect
respondents and found that in the tropical belt with similar who is now leading the most environment for analysis because
climate, rather than genetics, climates — Singapore, Malaysia, comprehensive adult allergy the problem-causing allergen
appears to have the most impact Indonesia and others — show cohort study conducted in [dust mites] is so specific.”
on sensitization. Andiappan similar reactivity to dust mites, Singapore, these findings were “We started out with a big
notes: “People who had just suggesting they had been nothing short of “spectacular”. exploratory study — we weren’t
arrived in Singapore from exposed before. People from He began to look more closely at even focusing on allergies at
mainland China seemed to temperate climates, such as the problem. the beginning,” says Rötzschke.
have a much lower prevalence mainland China and Hong Usually, Rötzschke says, “We effectively cast a net, and
of the house dust mite allergy Kong, generally become more allergy studies are complicated this fishing approach enabled
and allergic rhinitis symptoms sensitive to house dust mites by the sheer number us to build a huge database,
compared to those who had the longer they stay of factors so we could really dive into
stayed more than eight years.” in Singapore. that exploring immune responses
In some cases, he says, the Dust mites and genomics.”
difference was evident after thrive in the hot and Rötzschke points out that
just three years of living humid conditions urbanization and lifestyle
in Singapore. that are the norm changes — namely, spending
By contrast, there was in tropical zones. In more time in indoors — may
no significant difference in temperate climates, be the most significant factors
reactivity to dust mites between although they can behind an overall increase
Chinese people from Malaysia be a problem in the prevalence
and those born in Singapore. in the of airborne

During a bout of allergic rhinitis
(hay fever), white blood cells
respond to contact with allergens,
such as dust mite fecal matter, by
releasing histamine, which creates
swelling and inflammation.

© Kateryna Kon/Science Photo Library

Some people’s white blood cells don’t release
histamine, which recent A*STAR research suggests
might be related to stimulation of an inactive state in white
blood cells known as basophils. People whose basophils are
in an inactive state may not develop noticeable symptoms
and will probably never know they are allergic .

6 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

allergies in recent decades. seem to be self-diagnosing, he
This tendency to stay in dust says, and ignoring symptoms
mite friendly environments is PERCENTAGE OF SENSITIZED MIGRANTS FROM CHINA or taking over-the-counter
People from temperate climates, such as mainland China and
not limited to Singapore. “What Hong Kong, generally become more sensitive to house dust mites
antihistamines, which only
we are seeing here will become the longer they stay in Singapore. This suggests that this type of offer short-term relief. “As the
more relevant to other countries,” allergic reaction is exacerbated by exposure and not just genetics. house dust mite trigger doesn’t
Rötzschke says. “So, I consider this immediately lead to severe
a unique chance for us to become 80% reactions, people tend to be less
a world-leading center for cautious about it.”
allergy research.” It’s important Andiappan
advises, to get yourself properly
MANY WON’T KNOW 60% diagnosed via a skin prick or a
THEY’RE ALLERGIC blood test. “If you’re constantly
One intriguing conclusion exposed to the allergen over a
drawn from Andiappan’s 2014 long period of time, it could affect
40%
study was that not everyone who disease treatment adversely,
tests positive for the house dust so our recommendation is
mite allergy (roughly 80 per early diagnosis.”
cent) goes on to have symptoms 20% Following up with the group
(roughly 40 per cent). of people who ‘carry’ the allergy
In 2017, Rötzschke and his without adverse effects will
team made a breakthrough on be another crucial step for
protection from allergic rhinitis clinical research. This is where
0-3 3-8 >8 SINGAPOREAN
based on a phenomenon called the study of epigenetics —
basophil anergy. NUMBER OF YEARS IN SINGAPORE changes in gene expression
Basophils are cells in the that do not involve changes
blood that detect allergens and to your DNA — will become
Redrawn from Ref. 1 with permission from the European Academy of Allergy and Clinical Immunology (EAACI)

trigger allergy symptoms. In increasingly important.
some cases, these basophils already train their immune In the first large-scale study A curious side note is the fact
become inactive. This so-called system to respond better through of its kind in Singapore, Evelyn that Rötzschke himself says he
‘anergy state’ correlates with exposure to small doses of an Loo, co-workers at the Singapore does not have allergic rhinitis,
people who don’t develop allergen over long periods. Institute for Clinical Sciences even though he has been based
allergic rhinitis, which could be This method, called allergen- and collaborators at NUS, among in Singapore for the last decade
one explanation for why some specific immunotherapy, is others, found that wheezing after spending many years in
people whose Immunoglobin E widely considered to be the best and eczema before 18 months temperate climes both in Europe
antibodies levels would suggest treatment option for allergies. is associated with an increased and the in US.
that they are allergic, don’t To give sufferers the best risk of senzitisation to allergens, “I fall exactly into that
develop symptoms. chance of benefitting from such including house dust mites, at area where I’m supposed to
Rötzschke says that it’s treatment, more studies are three years of age. have a response to house dust
possible that this process of focusing on immune response They conclude that the mites, but I don’t. Why am I
shutting down basophils in early childhood to find ways common long-term effect of not allergic?” he asks. “It may
could provide a mechanism to predict the likelihood of impaired airway function caused be that my genetics renders my
for targeted treatment of allergic developing respiratory allergies by early-onset wheezing or basophils inactive.” This broad
rhinitis that involves “switching later in life. eczema might make children question is among the many
off” nasal allergies. For example, a study in more vulnerable when exposed things he and his team will
Sweden has shown that onset of to allergens in later life. investigate next.
EARLY RISK FACTORS eczema in the first year of life The earlier people pick up
No one knows yet if treatments was linked to increased risk of on dust mite allergy symptoms, For references, visit the online
version of this article at:
targeting basophils will become developing asthma and allergic the better, agrees Andiappan. https://www.research.a-star.edu.sg/
a reality, but some people can rhinitis later on. Most adults unfortunately feature-and-innovation/7832

www.research.a-star.edu.sg A*STAR RESEARCH 7
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

GREEN LIGHTS
ALL THE WAY

8 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

Taxis utilized to their full potential, intersections with
no traffic lights and devices that eliminate driver
error — anything is possible in Singapore, one of the
world’s busiest test beds for intelligent traffic

W
e could ble. Because of this coordinated
increase effort, Singapore — one of the
traffic densest cities in the world — sits
efficiency by at a comfortable number 55 in
up to 45 per TomTom’s congestion world
cent,” Yang Bo says, discussing ranking, well behind less pop-
a futuristic intersection without ulous cities such as Sydney, San
traffic lights he modeled at Francisco and Auckland.
A*STAR’s Institute of High
Performance Computing ELIMINATING TRAFFIC
(IHPC) last year. Creating LIGHTS FROM
smoother traffic flows could INTERSECTIONS
also save millions of liters of Yang proposed his lightless
fuel that would otherwise be intersection in 2017, along
consumed globally by vehicles with a colleague, Christopher
idling at traffic lights each Monterola. Cars would
day. Indeed, a lot of fuel and continuously move through
commuter time could be saved these junctions, and while
by implementing the many ideas human drivers still steer,
being modeled at the IHPC, acceleration, deceleration and
including several to improve interactions with other cars
the ‘hive brains’ guiding the are controlled by a beacon
movements of taxis and ride- installed on the dash and at the
sharing vehicles. intersection. He says
The IHPC is fortunate, as efficiency gains are found in
Singapore is a major test bed reducing redundant waiting
for intelligent transport systems. for light changes and human
Its roads pulse with information factors such as “phantom
and subtle adjustments: smart traffic”, in which drivers slow
intersections vary their cycles unnecessarily at the fringes of a
according to the flow of traffic congestion, with rippled effects
and intelligent ramp meters slowing cars upstream.
note the density of cars, while It’s a response to a hope-
a congestion tax, politically ful, but uncertain future as
contentious in other cities, is autonomous vehicles begin to
collected by electronic gantries penetrate the market, Yang says.
daily. This is all managed by the “The question is: How do we
city’s Land Transport Authority make a new system that has the
(LTA) — who has 164 kilometers least-required modification to
of expressways and road tunnel vehicles until we fully imple-
systems wired for data collec- ment driverless cars?” While
tion and video surveillance. The tech behemoths such as Didi
© Malorny/Getty

information is fed to operators and Google race to develop
who smooth flows and send systems to guide driverless cars
assistance to motorists in trou- through intersections, Yang says

www.research.a-star.edu.sg A*STAR RESEARCH 9
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LIGHTLESS
INTERSECTIONS
An intersection
proposed by Bo Yang
and Christopher
Monterola at the
Institute of High
Performance
Computing could see
cars flow through
continuously without
having to stop.

A cruise control-like
device installed in car.

A beacon or intersection
control device.

Vehicles are repulsed
by other vehicles.

the aim of his model is to make driverless will still be on the its simplest, Yang’s intersection highly localized, this system
something practical today and roads,” he points out.    only require that vehicles to be at is also easy to implement and
for the anticipated “long transi- In 2016, the world’s first driv- Level 1 — the intelligent car bea- requires minimal energy to run.
tion period” to fully driverless erless car policy emerged from con could take over some aspects Yang adds that his modeling of
technology. “If you have a high the United States and outlined only in the intersection ‘zone’ the intersection sees overall
technological barrier, say you five levels of autonomous vehicle and would protect passengers efficiently gains even if today’s
© shanghaiface/Getty

have a system that needs an ranging from regular cars with using an algorithm that was cars (he calls them ‘legacy
autonomous vehicle, it’s going driver assistance (Level 1) to designed to create a mathemati- cars’) make up 70 per cent of
to take a long time to imple- fully automated machines with cal repulsion between vehicles.  the traffic. He explains that
ment, because cars that aren’t no steering wheel (Level 5). At Because the zone would be for today’s vehicles, these

10 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

account for vehicle-pedestrian Computing and Engineering vehicles will often pass a num-
interaction, Yang’s intersec- Corporate Lab in a collaboration ber of potential passengers to get
tion is still theoretical. But in between A*STAR, technology to a booked passenger.
Singapore, ideas like this can be- giant Fujitsu Limited (Fujitsu) The IHPC collaboration
come reality; the city’s advanced and the Singapore Management soon spawned an app using
thinking on the road means University (SMU). Zheng’s team FALCON.Amy, called the Driver
it has bucked dominant world used the taxi data to train a Guidance System (DGS). Within
trends and actually improved its learning neural network they the year, the app was already
congestion levels in recent years. devised — called Fusion directing taxis to roads where
The red carpet is also being Architecture for Learning and they’re likely to find a fare, and
laid out for companies diving Cognition with Alternative being used in the National Taxi
into the autonomous vehicles MemorY (FALCON.Amy) — Association (NTA) SkillsFuture
market by the Singapore Auton- to predict pick-up hotspots for Training Programme.
omous Vehicle Initiative (SAVI), taxi drivers. Zheng says Singapore’s
a joint partnership between the taxi association is big supporter
LTA and A*STAR. They see Sin- of the project. “They are very
gapore as the logical home for anxious to improve technology
the world’s driverless statutory TIMES CHANGE FOR TAXIS for their drivers,” he says. While
Singapore’s average daily taxi ridership
and technical firsts. At the mo- fell to 785,000 last year, an 18-per
reducing empty taxi roaming
ment, there are only a handful cent drop from 2016 according to data alleviates congestion by decreas-
of official city-based driverless from Land Transit Authority. ing unnecessary road use, it
trials in the world; this year AVERAGE DAILY TAXI RIDERSHIP
could also boost profitability
Singapore will host both the for taxis struggling in an
2016 954,000
world’s first driverless taxi trials era when disruptive technol-
for the MIT spin-off nuTonomy 2017 785,000 ogies are cutting into their
and commercial driverless car bottom line.
tests for electronics and software The DGS was primed to pre-
company, Delphi Technology. However, the results of a survey dict fare locations using roughly
published by the Public Transport
Council in February show satisfaction
two years’ worth of taxi data.
OPTIMIZING TAXI ROAMING with taxi services has improved Numbers from a free trial for taxi
This forward-thinking approach despite lower ridership. The number of drivers showed significant im-
commuters satisfied with taxi services
to its roads is typical. For rose 4 per cent between 2016 and
provements for cab drivers during
decades now, Singapore’s 2017, and the mean satisfaction score off-peak hours; those using the
government has been increased by 0.4 points. app decreased their average emp-
extraordinarily clever with its MORE COMMUTERS SATISFIED
ty roaming time between fares in
road data. For example, each the city between midnight and
of the city’s more than 20,000 2016 94.4%
6am from 17 to 12 minutes. 
taxis are required to transmit 2017 98.5% Early feedback, collected
its GPS location and working through discussions with driv-
status every 30 seconds to the COMMUTER SATISFACTION SCORE
ers who participated in the trial,
LTA, so that it can monitor a was also predominantly positive,
key mode of transport in a city 2016 7.5 / 10
particularly for new taxi drivers
where fewer than one in 10 own 2017 7.9 / 10 who don’t already know where
a private car. Some of this data to find fares. However, some taxi
intersections mean using a is also being harnessed by the drivers reported a reluctance to
system similar to when a IHPC to come up with ways to miss out on booking fees.
driver stops and waits for the improve taxi occupancy. At peak demand, these street This doesn’t bother Zheng.
right moment to cross when In 2016, a team led by Qin pickups become much more While, it seems that companies,
he or she sees a stop sign. The Zheng, a senior scientist also at efficient than bookings systems, such as Uber and Grab are here
caveat is “it will be a little slower the IHPC, started by looking at which include disruptors such to stay for the mid-term, he says
Source: data.gov.sg

for older cars, but that will a week’s worth of taxi data. To as Uber and Asian counter- the long-term thinking is that
encourage people to upgrade.”  examine the 3.6 million-odd parts, Grab and Didi. IHPC and they will be used for another five
Without real-world data points, they worked other studies have shown that in to ten years, after which the city
implementation and data to with the Fujitsu-SMU Urban high-demand conditions, will move to driverless taxis.

www.research.a-star.edu.sg A*STAR RESEARCH 11
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

“Imagine there are no drivers;
then all we want is to optimize
the social benefit,” he says. In
that future scenario, systems, “Our results
including the one Zheng’s team show that
trained for this project, will
be less constrained by individu- a good
al drivers’ needs and could form algorithm
a part of very efficient future
traffic systems run largely by for taxi ride-
advanced algorithms and sharing can
artificial intelligence.
However, in countries such really help.”
as Fujitsu’s country of origin,
Japan, the data they need to
train a system like Zheng’s will
have to be drawn from a wider
variety of stakeholders than in help,” he explains, “because
Singapore, including a number increased ride-sharing is not
of different taxi or transport only for the common good, but
companies. But, while can also be immediately helpful
Singapore has one of the world’s to individuals as well.”
most centralized traffic data A culture of hyper-organ-
sources, the base information ized solutions has always been
needed to run Zheng’s program Singapore’s strategy for dealing
exists in any city with GPS- with limited space. As the world
linked taxi-like services. “If we approaches a watershed for
can get hold of Uber or Grab driving technology, a dense
data we can apply it,” he says.  and still fast-growing popula-
tion means that Singapore is
COULD THERE BE 60 PER incentivised to remain the
CENT FEWER TAXIS? Various innovations may lighten traffic by reducing the numbers of taxis needed world’s most cutting-edge place
Yang adds that increasing on the road. However, the financial returns for taxi drivers could also increase if for intelligent traffic.
they are able to carry multiple, separately paying passengers at once and are able
vehicle sharing has the potential The government also
to be occupied for a greater percentage of the working day.
to further winnow traffic. One continues to invest heavily
2015 study showed that in New in advanced technology: in
York, assuming people were still in the process of looking at demand. His model suggests 2016, for example, the LTA
willing to share taxis whenever lots of information, particularly that during busy periods, gains announced a new S$556 million
possible, taxi demand could be traffic conditions and commuter in shorter wait times could (US$423 million) project to
reduced to just 15 per cent of the boarding and alighting behav- far outweigh the time cost of install units into all Singaporean
current fleet. iours.” That’s their next step, he accommodating another taxi cars so a satellite tracking sys-
In Singapore, says Yang, if says, “adding more and more passenger, not to mention the tem can determine congestion
a ride-sharing algorithm he and information to make the simu- real cost savings. fees and automatically deduct
his colleagues have developed  lation more accurate.” Yang also Taking all of those taxis off charges for curb-side parking.
© Charles Pertwee/Bloomberg via Getty Images

were to be adopted by 50 per points out that “the tricky thing the road will also reduce traffic Driverless cars are perhaps still
cent of taxis — in a system in about Singapore it is that it’s a and travel times, says Yang. a decade away, but Singapore
which more than one person is relatively rich society, so people But those benefits will only and its researchers are position-
an individual paying passen- don’t really want to give up their become evident if advanced ing themselves as front runners
ger — the 15,000 taxis on the privacy to save a few dollars.” modeling like the IHPC’s “can in the road race towards the
road at any one time could be But Yang’s work shows that convince policy-makers to smartest cities of the future.
reduced to 6,000. ride-sharing taxis may find a cultivate a culture of ride
But he’s quick to explain foothold during peak hours sharing”, he says. “Our results For references, visit the online
version of this article at:
that this number needs to be and bad weather, when passen- show that a good algorithm https://www.research.a-star.edu.sg/
taken with a grain of salt: “We’re gers are faced with surges in for taxi ride-sharing can really feature-and-innovation/7831

12 A*STAR RESEARCH  Issue 10 | January – March 2018
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MANUFACTURING

SiO2 2.0μm

A BETTER ANGLE ON 69.4° 68.6°
MICROSCOPIC DEVICES
1.3μm
A flexible, low-cost technique could Si
lead to the mass production of
microelectromechanical systems
for use in a range of applications Tapered contact opening fabricated by new two-step plasma etching process.

Making increasingly small mass production of smaller and at scales of five microns or during the etching process —
microelectromechanical systems more reliable devices for a range less, are not dependable. The accelerated corner sputtering
(MEMS) has proved very chal- of new applications. etching method, with sidewall and sidewall polymerization,”
lenging, limiting their anticipat- polymerization, is not suitable explains Bliznetsov.
ed potential. Now, researchers at Combining these as the width at the bottom of Combining these processes
A*STAR have developed a versa- processes into a the vias shrink considerably. into a two-step method achieves
tile and cost-effective technique two-step method Another method, involving the greater control over the etching
for making devices with much achieves greater transfer of a photoresist profile process and produces micron-
greater precision and reliability control over the into an etched layer, limits the sized vias with smooth, tapered
for use in biotechnology and maximal depth of vias due to walls. And by minimizing the
etching process
medical applications.1 excessive loss of the photoresist sidewall angle of the vias, it is
MEMS are used in
and produces mask resulting in unacceptably possible to fabricate devices
applications ranging from airbag
micron-sized vias rough sidewalls. that can be better protected
systems and display screens to with smooth, To overcome these restric- and have more reliable metal
inkjet cartridges. They are tiny tapered walls. tions, the researchers developed contacts, greatly improving their
devices that combine mechanical a two-step plasma etching performance.
and electrical components. “MEMS are following the process. This combines firstly “Precise control of
Current manufacturing general trend of miniaturization photoresist tapering, which sidewall angle has use in many
© 2017 IEEE. Reprinted, with permission, from Ref 1.

technologies, however, are in electronics, with devices that modifies the photoresist from applications, and we are now
expensive and lack the precision are reducing in size from the a vertical to a tapered profile, planning to fabricate functional
for making devices with micron tens of microns to one micron and then an oxide etching with magnetic memory cells, which
and sub-micron scale features. or less,” says Bliznetsov. “But the sidewall polymerization with require pillars of magnetic
This led Vladimir Bliznetsov techniques used to manufacture better selectivity to photoresist. material with sidewalls having a
and colleagues from the A*STAR top metal contacts to devices This produces vias with minimal specific angle,” says Bliznetsov.
Institute of Microelectronics to with such microscopic dimen- dimensions down to 1.5 microns,
1. Bliznetsov, V., Li, B., Lee, J. W., & Lin,
develop a versatile and low-cost sions are costly and unreliable.” and smooth sidewalls with an-
H. MEMS industry-worth etching to
method for fabricating MEMS Current methods for creating gles of around 70 degrees. fabricate tapered structures in SiO2 .
at dimensions not previously channels, called vias, with “We combined two effects Journal of Microelectromechanical
Systems 26, 1400–1407 (2017).
possible, edging closer to the tapered sidewalls in MEMS which are usually harmful

www.research.a-star.edu.sg A*STAR RESEARCH 13
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A powerful solution to the The coating consisted of an
global spread of antimicrobial array of tiny, positively charged
resistance could soon become dagger-like crystals that
available, thanks to A*STAR grew perpendicularly to the
NANOMEDICINE researchers, who have come substrates.
up with a physical and “We used inexpensive
environmentally friendly materials and a simple method
alternative to biochemically to create this nano-dagger
active antibacterial agents. structure on different types of
Typically transmitted by surfaces,” says Zhang noting that
contact with contaminated his team had to try numerous
surfaces, bacterial infections formulas before finding the right
TAKING A STAB pose serious health threats growth conditions.
AT MICROBES in medical settings. Small
molecular antibacterial agents,
Regardless of the coated
substrate, the nano-dagger
Arrays of tiny, rigid, and sharp which are commonly used arrays effectively killed
in antiseptics, disinfectants, the antibiotic-resistant
pillars mimic natural antimicro- and preservatives, and other bacteria Escherichia coli and
bial surfaces by binding and consumer care products, Staphylococcus aureus as well
breaking bacterial cells open can prevent cross-infection as the fungus Candida albicans,
by annihilating bacteria on demonstrating their broad
frequently touched surfaces. applicability. They also retained
However, their overuse their antibacterial activity when
contributes to antimicrobial exposed four consecutive times
resistance. These toxic and to E. coli over two months,
persistent substances can proving their durability.
also harm the environment According to Zhang, the
by disrupting the ecological positive charges positioned on
balance of soils and the nano-daggers first attract
endangering aquatic life. bacterial cells that bear negatively
In response to this, Yugen charged membranes, making
Zhang and Yuan Yuan, from them stick to the coated surface.
the Institute of Bioengineering Next, the sharp nano-dagger
and Nanotechnology have tips rip the cell membranes
developed nanostructured open through electrostatic and
surfaces that destroy bacteria gravitational forces.
through physical, rather than “We are really excited about
biochemical interactions. These the excellent bacterial killing
surfaces mimic the antimicrobial property of this technology and
patterns formed by ultra-small believe that it will have wide-
pillars on cicada wings. “In ranging applications in real
© 2018 A*STAR Institute of Bioengineering and Nanotechnology

addition to being clean and safe, life,” says Zhang. His team is
this technology does not require currently working on developing
externally applied chemicals,” nano-dagger surface prototypes
says Zhang. and other antimicrobial
The researchers added a nanopatterned surfaces using
zinc-based solution to various different materials.
surfaces, including rubber,
glass, wood, and metal foil, 1. Yuan, Y. & Zhang, Y. Enhanced
biomimic bactericidal surfaces by
then immersed the surfaces in
coating with positively-charged ZIF
an aqueous solution containing
nano-dagger arrays. Nanomedicine:
amine-rich 2-methylimidazole Nanotechnology, Biology, and
A*STAR researchers have developed positively charged nano-dagger arrays to form a so-called zeolitic Medicine 13, 2199–2207 (2017).
(pictured) that effectively kill microbes, such as E. coli and Staphylococcus aureus. imidazolate framework coating.

14 A*STAR RESEARCH  Issue 10 | January – March 2018
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THERAPEUTICS

SHEDDING ‘LIGHT’
ON ANTIBODY
DESIGN
The light chain
subunits of therapeutic
antibodies impact drug The light chains of Y-shaped antibody
molecules (shown here in blue) impact
performance and yield drug performance and yield.

Antibody-based drugs target molecules and that the from a recombinant cell culture its framework regions can
have long been a mainstay of ‘framework’ regions of light system, although it did not impact key factors of a good
treatment for many conditions, chains provide structural severely affect the ability of therapeutic antibody, even at
especially cancer and support to allow target contact. trastuzumab to bind its target, a sites that are not known to be
autoimmune diseases, but there protein called human epidermal directly involved in binding or
may still be room for improving growth factor receptor 2 (Her2). purification,” he says.
‘‘The light chain
these complex biological Delete both amino acids, Although these initial
therapies. An A*STAR study has
and its framework however, and both antibody findings demonstrate only
found that changes to a part of
regions can impact production and Her2 binding the negative consequences
antibodies that’s often overlooked key factors of a decreased significantly. of altering an antibody’s
by protein engineers and drug good therapeutic Structural modeling light chain, Gan and his team,
companies can have dramatic antibody.’’ and experiments conducted in work not yet published, have
effects on target binding and by members of Gan’s also found ways to enhance
manufacturing yield. To evaluate the importance Antibody Product and both production and target
An antibody is made up of the light chain in antibody Development lab, including binding through other light
of four polypeptide chains: performance, a team led by co-first authors Chinh chain modifications. “This
© PIXOLOGICSTUDIO/SCIENCE PHOTO LIBRARY/Getty

two ‘heavy’ chains form the Samuel Ken-En Gan from Tran-To Su and Wei-Li Ling, is only the first in a series of
Y shape of the molecule, and the A*STAR Bioinformatics revealed that the deletions papers from my lab to show
two ‘light’ chains sit alongside Institute and the p53 impaired the interaction that we need to consider the
them. To date, most of the Laboratory deleted two amino between trastuzumab and antibody as a whole and not
modification techniques in acids in the framework region of a protein used for antibody just as a sum of different
therapeutic antibody design the light chain of trastuzumab, purification. That explains the parts,” Gan says.
have focused on the heavy an antibody drug for treating yield reduction, while decreased
1. Su, C. T., Ling, W. L., Lua, W. H.,
chains. The light chains were breast cancer, sold under affinity for Her2 explains why
Poh, J. J. & Gan, S. K. The role of
generally considered less the brand name Herceptin. the deletions also obstruct Antibody Vκ Framework 3 region
important, even though it Either deletion on its own, antibody performance. towards Antigen binding:
Effects on recombinant production
has been demonstrated that the researchers found, led to a “This study shows and Protein L binding.
they’re also involved in binding reduction in antibody secretion that the light chain and Scientific Reports 7, 3766 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 15
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Illustration of zika viruses
attacking a neuron.

A new test for the Zika significantly since the major
virus could help limit future outbreak in the Americas in
outbreaks, especially in areas 2015-16, outbreaks are thought
without access to sophisticated to be cyclical.
INFECTIOUS diagnostic methods. The current gold standard
DISEASES
An international team led diagnostic test identifies the
by Lisa F. P. Ng of the A*STAR presence of Zika virus RNA in
Singapore Immunology blood or urine. To be sure of
© KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty

Network found that an existing detecting infection, however,
flow cytometry technique can blood samples must be taken
accurately detect the presence of within seven days of the onset

A NEW WEAPON a key Zika virus antigen.
Most people infected with
of symptoms or within 14 days
for urine. There are also tests for
AGAINST THE ZIKA VIRUS the mosquito-borne virus have antibodies against the virus in
no symptoms or very mild blood, but these tests can fail to
An existing laboratory technique can effects. However there is strong distinguish Zika from closely-
detect Zika virus infection and may help evidence that it can cause severe related flaviviruses like dengue.
birth defects. While the number A team of researchers from
make diagnostic tests more accessible
of new cases has dropped Singapore, Estonia and Russia

16 A*STAR RESEARCH  Issue 10 | January – March 2018
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made a synthetic version of NS3,
a protein that helps the Zika
virus replicate. They injected
these proteins into rabbits to
generate NS3 antigen-specific
FLUID
DYNAMICS
antibodies, which they then
added to blood samples taken

© 2018 A*STAR Institute of High Performance Computing
from 47 Zika patients at Tan
Tock Hospital in Singapore.
The researchers used a flow
cytometry technique called
fluorescence-activated cell
sorting (FACS) to measure COMPUTING
the proportion of white blood
cells containing Zika virus
THE EBB
antigen in the patient samples. AND FLOW
After tests on samples from
healthy controls, the group set Designing deep-sea oil
the threshold for Zika virus rigs could be improved by
The interaction between waves and the wide legs below a
infection at 0.5 per cent.
simplified wave simulations floating structure, as indicated above, is complicated.
Detection rates of less than
10 per cent, 10–40 per cent and
more than 40 per cent were
characterized respectively as low,
medium and high. Evaluating the impact of made it possible to solve the pling the subdomains is diffi-
All the samples from patients waves on deep-sea oil rigs complicated three-dimension- cult. Lu and the team achieved
in the high detection group were has been made easier by an al nonlinear equations that this coupling by overlapping
taken between two and five days A*STAR-developed computa- describe fluid flow around and the regions in what they call
after the onset of symptoms, tional technique that should through a complex arrange- buffer zones. “This overlapped
suggesting this may be the increase the operational lifetime ment of objects. But the calcula- zone technique eliminates the
optimum window for the test. of floating platforms and make tions are time consuming, and need for sub-iteration in each
Further tests also showed the them cheaper to manufacture. engineers must often make a time step, thus speeding up the
technique can differentiate between Offshore oil platforms and compromise between accuracy modeling,” explains Lu.
Zika virus and similar viruses. wind turbines conventionally and efficiency. To address this The team use their over-
“The current detection rest securely on the seabed. trade-off, Xin Lu and co-work- lapping domain decomposi-
methods all have limitations,” But if they are to operate in ers from the A*STAR Institute tion technique to model the
says Ng. “Using FACS to detect deeper waters, floating struc- of High Performance Comput- propagation of a solitary wave,
Zika virus NS3 antigen in the tures are required. Given the ing developed a method that to measure the impact of the
blood could offer a relatively enormous investment needed reduced computing time by wave on a partially submerged
efficient and fast complementary to build and position these plat- building on a technique known body and to recreate a wave
method. It can be done using forms, it is essential that they as domain decomposition. as it breaks on a beach. “This
fresh blood samples and requires can withstand waves, storms Their method divides new method is able to deliver
minimal processing, and so and even tsunami. Potential the area to be simulated into comparable results in just half
could be especially useful in designs are typically tested by subdomains in which differ- or even a third of the original
settings where there is no access building a model and trialing ent types of calculations are computing time,” says Lu. “And
to the equipment and trained it in a wave tank — but this is performed: a near field subdo- when optimized, the computing
technicians required by current expensive, and results obtained main in which the viscous flow time is expected to be further
molecular tests.” under such controlled condi- model is applied, and a far- reduced by 80 per cent.”
tions are not always transfera- field domain in which a model
1. Lum, F.-M., Lin, C., Susova, O. Y., 1. Lu, X., Denver, D., Chandar, J., Chen,
ble out at sea. that calculates the system’s
Teo, T.-H., Ng, L. F. P. et al. Sensitive Y. & Lou, J. An overlapping domain
detection of Zika virus antigen Computer simulations potential energy is applied. decomposition based near-far
in patients’ whole blood as an provide a cheaper approach. The computational effort per field coupling method for wave
alternative diagnostic approach. structure interaction simulations.
Journal of Infectious Diseases 216, The rapid development of high subdomain is much smaller Coastal Engineering 126, 37–50
182–190 (2017). performance computers has than the full domain, but cou- (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 17
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An immune cell
involved in brain
IMMUNOLOGY defense, called a
microglia, made
from a stem cell–
derived macrophage.

USING A MOUSE
TO MAKE AN ‘IMAC’
A new method for making
specialized immune cells from stem
cells offers a tool for modeling
inflammatory diseases in the lab

A specific type of white blood These iMacs were genetically into a type of immune cells, characterized by macrophage
cell, considered the sentinel of and functionally similar to known as microglia, involved in dysregulation in different organ
the immune system, can now be early macrophages found in brain defense. systems. For example, the iMicros
made in almost limitless volumes the developing embryo. And could help scientists shed light
in the laboratory. by making iMacs from the These cells provide on the immune contributions
A two-step protocol, iPSCs of someone with Familial a tractable systen to neurodevelopmental
developed by A*STAR researchers, Mediterranean Fever, a rare for studying the disorders such as autism and
for turning reprogrammed stem inherited autoimmune disease, ways in which a neurodegenerative disorders such
cells into various types of tissue- they showed that these cells as Alzheimer’s disease.
genetic disease
specific white blood cells, known provide a tractable system for “[These cells] will provide
as macrophages, could help studying the ways in which
can cause immune insights into the mechanism
scientists design new medicines a genetic disease can cause
signalling to go of primitive macrophage
for inflammatory diseases of the immune signaling to go awry. awry. maturation into microglia,”
lungs, brain and other organs. Ginhoux’s team next coaxed says Ginhoux. “Furthermore,
The first step in the the iMacs to form the kinds of The researchers could also the co-culture model has the
process involves converting mature macrophages found in form these lab-made microglia potential to serve as an in vitro
© 2018 A*STAR Singapore Immunology Network

induced pluripotent stem different tissues of the adult — or iMicro cells, as they called drug screening system for the
cells into a kind of primordial body. In one experiment, the them — by implanting iMacs development of novel therapies
macrophage. Florent Ginhoux researchers mixed the iMacs in directly into the brains of against brain diseases.”
and his colleagues at the a lab dish with neurons that had newborn mice. Putting iMacs into
A*STAR Singapore Immunology also been made from the same the lungs of mice also resulted in 1. Takata, K., Kozaki, T., Lee, C. Z. W.,
Thion, M. S., Otsuka, M. et al. Induced-
Network devised a recipe for batch of iPSCs. After about a lung-specific macrophages. pluripotent-stem-cell-derived primi-
doing this with either mouse or week of co-culturing, the iMacs With the protocols all worked tive macrophages provide a platform
human cells, creating what they started to develop tentacle-like out, these kinds of tissue-resident for modeling tissue-resident mac-
called iPSC-derived primitive projections called dendrites, immune cells now provide a rophage differentiation and function.
Immunity 47, 183–198.e6 (2017).
macrophages — or simply iMacs. suggesting they had morphed valuable tool for studying diseases

18 A*STAR RESEARCH  Issue 10 | January – March 2018
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GENETIC
DISEASE

OF MICE
AND MEN
A rare mutation
causes severe growth
A*STAR
retardation and spine researchers
malformation in have uncovered
a genetic mutation
humans and mice that causes severe growth
retardation in humans and mice.

Mutations in a gene associated growth retardation and some mice. A significant number of developed longer cilia than the
with cellular proliferation skeletal defects that resemble these genes are involved in lipid healthy controls. The functional
cause a newly described those observed in patients metabolism which suggests that consequences of Cdk10’s effect
disease characterized by severe with CDK10 mutations, or the impaired conversion of fats on cilia, however, remain to be
growth retardation, spine what has been termed Al Kaissi into energy may underlie the investigated.
malformation, dysmorphic Syndrome. “The mouse model growth retardation observed This study is a great example
facial features and intellectual provides compelling data that in mice and humans bearing of how mouse models contribute
disabilities, according to an CDK10 is the gene causing CDK10 mutations. This raises the to our understanding of human
international study led by disease, and confirms the potential for mitigating some of developmental disorders.
A*STAR researchers. human genetic data” said the features associated with Al “Without the mouse model that
The team found that nine Philipp Kaldis, at the A*STAR Kaissi Syndrome through dietary recapitulates some of the features
individuals from five unrelated Institute of Molecular and Cell interventions. of Al Kaissi Syndrome we would
families in Turkey, Algeria, Biology and lead author of not have uncovered a new role
Tunisia and Saudi Arabia with the study. “Without the for CDK10 in cilia growth and
identical clinical features all Despite Cdk10 being mouse model we metabolism” explains Kaldis.
carry mutations that inactivate an essential gene for mouse would not have Identifying the genetic causes
the cyclin-dependent kinase 10 development, fibroblast cells of rare conditions not only helps
uncovered a new
(CDK10) gene. Mutations are from Cdk10-deficient mice and physicians with diagnoses, but
role for CDK10 in
rare in CDK genes, which encode from patients divided normally offers researchers a starting point
proteins that regulate cell growth when isolated and grown in the
cilia growth and for developing new treatments.
and division and are carefully lab. However, analyses of various metabolism.”
kept in check to prevent tumor organs revealed multiple defects 1. Windpassinger, C., Piard, J., Bonnard,
C., Alfadhel, M., Lim, S. et al. CDK10
formation. in the mice lacking Cdk10. In the The expression of genes mutations in humans and mice
To investigate the effects of affected organs (which included involved in the formation of cause severe growth retardation,
© rubberball/Getty

losing the function of CDK10, kidneys, lungs, brain, intestine tiny hair-like, sensory cellular spine malformations and develop-
the researchers generated and muscle) more than 600 protrusions called cilia was mental delays. The American Journal
of Human Genetics 101, 391–403
mice lacking the Cdk10 gene. genes were expressed differently affected in organs of Cdk10- (2017).
These mice displayed severe compared with healthy control deficient mice — their fibroblasts

www.research.a-star.edu.sg A*STAR RESEARCH 19
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GUT BACTERIA different group of immune cells
called macrophages, which
IMPLICATED IN LIVER are increasingly recognized as

INFECTIOUS INFLAMMATION significant in liver disease.
They analyzed the
DISEASE
The effect of gut bacteria on specific molecular and functional
profiles of macrophages in
immune cells is behind persistent liver the livers of patients with
inflammation in chronic viral hepatitis chronic viral hepatitis and
those of healthy people. In
the livers of patients, there
was an excess of macrophages
with a specific profile that
Persistent liver inflammation in the mechanism that maintains NUS Medical and Singapore promotes inflammation. “Unlike
sufferers of chronic viral hepatitis this inflammation has been Institute of Clinical Sciences, macrophages found in a healthy
is likely caused by interactions poorly understood. The degree the laboratory of Qingfeng liver, these macrophages have the
between pro-inflammatory of inflammation does not Chen at the A*STAR Institute of capacity to continuously produce
immune cells in the liver and correspond to the extent of viral Molecular and Cell Biology and pro-inflammatory mediators
products from gut bacteria, activity in the liver, or to the Charles-Antoine Dutertre in the when they encounter bacterial
according to new work involving activity of immune cells that laboratory of Florent Ginhoux products,” explains Dutertre.
A*STAR researchers. The findings specifically target the virus, as from the A*STAR Singapore The team studied this
identify new therapeutic targets. might be expected. Immunology Network, aimed phenomenon further in mice
Chronic viral hepatitis is The new work, a collaboration to determine the mechanisms engineered to have human
characterized by persistent between the laboratories of underpinning the inflammation. liver cells and human immune
inflammation of the liver, but Antonio Bertoletti at the Duke- The researchers focused on a cells. The mice were infected

Persistent inflammation
in the liver in chronic viral
hepatitis has been only
partially explained, but
these findings show that
gut bacteria causes pro-
inflammatory immune cells
to accumulate in the liver.

©KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty

20 A*STAR RESEARCH  Issue 10 | January – March 2018
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with hepatitis B virus, and
consequently accumulated
the same pro-inflammatory A CATALYST FOR CHANGE
macrophage population
in the liver as that seen
CHEMISTRY & IN CHEMICAL ETCHING
MATERIALS
in patients. Treatment of A simple, versatile and low-cost technique for
the mice with antibiotics etching nanoholes in silicon could underpin
to reduce the gut bacteria
reversed the accumulation new filtration and nanophotonic devices
of these macrophages.
“This demonstrated that
bacterial products that
leak from the gut into the
liver are responsible for the Metal-assisted chemical etching, on the catalyst cause it to move The researchers investigated
accumulation of the pro- or ‘MacEtch’, is used to fabricate during the etching process, which isolate catalyst etching of regular
inflammatory macrophages,” a range of nanostructures, limits their use in the fabrication gold disks of identical array
says Dutertre. but movement of the catalyst of structures with high aspect spacing and catalyst thickness,
The results identify during vertical etching processes ratios, such as nanoholes. formed using laser interference
a novel mechanism that hamper its wider use. Now, “Previously, it has been very lithography. This allowed the
maintains inflammation a team led by A*STAR have difficult to achieve directional team to study precise and
in chronic viral hepatitis. developed a technique that isolate catalyst etching, and [this] isolated effects of the etching
Dutertre and colleagues say improves catalyst stability, paving has been a major roadblock in parameters, such as the etchant
that their findings suggest the way for wider application.1 its development,” explains Sing and doping concentrations, to
new therapeutic approaches, MacEtch is a wet etching Yang Chiam from A*STAR’s understand the interface forces
in addition to targeting method for fabricating Institute of Materials Research on the catalyst.
the virus, that involve nanostructures from patterned and Engineering. “Small feature They found that higher ratios
modifying the intestinal metal film. The simplicity, sizes are especially important of hydrofluoric acid to hydrogen
bacteria or depleting the pro- versatility, and cost effectiveness for fabricating filtration devices, peroxide, or higher p-type silicon
inflammatory macrophages of MacEtch in silicon and other but at these dimensions, etching doping levels, reduce catalyst
in the liver. semiconductors have led to its becomes very challenging.” motion, and attributed this to
The researchers are use in the manufacture of a Now, a technique for a lowering of the interface Van
now investigating the wide range of products, from controlling the catalyst during der Waals forces caused by the
mechanism behind the electronic and optoelectronic the etching process, allowing creation of porous silicon.
effects of bacterial products devices to biological and for the fabrication of nanoholes The researchers
on macrophages in the liver. chemical sensors, as well as in silicon with unprecedented demonstrated their technique by
So far they have identified energy harvesting technologies. aspect ratios, has been developed fabricating large-area, regularly
certain soluble mediators These applications, however, use by Chiam and colleagues in ordered, nanoholes arrays in
that play a pivotal role. relatively large mesh catalyst collaboration with the National silicon with an aspect ratio of
“Our hypothesis is that by structures. University of Singapore and the around 12. This new method
inhibiting these soluble When catalysts with smaller University of Illinois at Urbana− enables the fabrication of new
mediators, we could limit dimensions are used, forces acting Champaign in the United States. biological and water filters, and
© 2017 A*STAR Institute of Materials Research and Engineering

the accumulation of the pro- nanophotonic devices.
inflammatory macrophages An example of directional etching for nanohole arrays of less than 500nm in diameter.
“We plan to use our findings
and resolve liver to make a simple filtration
inflammation in patients device, and then see how
with chronic viral hepatitis,” much further we can take deep
concludes Dutertre. trenching,” says Chiam.

1. Tan-Garcia, A., Wai, L. E., 1. Kong, L., Zhao, Y., Dasgupta, B., Ren,
Zheng, D., Ceccarello, E., Jo, Y., Kedar, H. et al. Minimizing isolate
J. et al. Intrahepatic CD206+ catalyst motion in metal-assisted
macrophages contribute to chemical etching for deep trenching
inflammation in advanced viral- of silicon nanohole array. ACS Applied
related liver disease. Journal of Materials & Interfaces 9, 20981–
Hepatology 67, 490–500 (2017). 20990 (2017).

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Two ‘finger-like’ proteins Ernesto Guccione, of
employ different mechanisms A*STAR’s Institute of Molecular
to help safeguard the ability and Cell Biology, and colleagues
of embryonic stem cells to throughout Singapore
STEM CELLS differentiate into a variety of cell investigated the roles of two
types, according to an A*STAR- PRDMs, PRDM14 and PRDM15,
led study. This finding could help in mouse embryonic stem cell
researchers develop new ways to (ESC) development.
regenerate lost or damaged tissue. They found that both
PRDMs are a family of proteins were critical for ESC
17 proteins with finger-like self-renewal — the process that
KEEPING STEM structures that contain zinc, maintains their ‘naïve state’,

CELLS NAÏVE
which are involved in regulating allowing ESCs to perpetuate
gene expression and modifying the stem cell pool and mature
the structure of chromatin, into any cell type — but that
Two proteins maintain embryonic stem cell the material that forms they did this through different
pluripotency through different means chromosomes. mechanisms.

© xxxxxxxxxxxxxx

22 A*STAR RESEARCH  Issue 10 | January – March 2018
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PRDM14 helps keep stem ‘‘Our findings could details of what happens within Guccione and his colleagues
cells naïve by turning off a group be incorporated embryonic stem cells when three are now collaborating with
of genes, called DNMTs, which into the routine different signaling pathways are geneticists to investigate whether
code for a family of enzymes screening switched on and off, but much mutations in PRDM15 lead
that add methyl groups to DNA. strategies for remained unknown about the to developmental defects in
PRDM15, however, was not ‘upstream’ factors, including those humans. “We think our findings
families showing
involved in DNA methylation. discussed in this study, that affect could be incorporated into the
developmental
The team found that PRDM15 these pathways. Understanding routine screening strategies for
conserved the naïve state of ESCs
defects.’’ these signaling pathways is families showing developmental
by turning on genes involved important for determining defects,” he says.
in regulating two signaling distinct targets, have evolved optimal culturing conditions
pathways that communicate how to regulate similar pathways, for mouse ESCs, understanding 1. Mzoughi, S., Zhang, J., Hequet, D.,
Teo, S. X., Fang, H. et al. PRDM15
the cell should function. in a non-redundant fashion, to the cues that regulate normal
safeguards naïve pluripotency by
“I found it interesting, from prevent embryonic stem cell embryonic development in living
transcriptionally regulating WNT
an evolutionary standpoint, that differentiation,” says Guccione. organisms, and finding ways to and MAPK-ERK signaling. Nature
different members of the same Previous studies had reprogram the body’s cells to Genetics 49, 1354–1363 (2017).
family, which bind to completely determined ‘downstream’ regenerate other tissue types.

© Fotosearch/Getty

A*STAR researchers find that two proteins
belonging to the same family maintain
embryonic stem cell pluripotency, but
© xxxxxxxxxxxxxx

through different mechanisms.

www.research.a-star.edu.sg 
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for third parties. “Now, we’ve
confirmed that a technique
called information flow analysis
can reveal decryption keys for
current and future versions of
chat-apps, assuming the app
design and use of external
encryption libraries stay the
same,” added her colleague,
Zhongmin Dai.
This information flow
analysis technique is used
in mobile forensics to filter
pertinent details from the
vast volumes of data flowing
within devices. Using this
method, Thing’s team was able
A*STAR researchers have to pinpoint the decryption keys
successfully determined for both apps, even though
the decryption keys the chat-apps used different
for both WhatsApp and
WeChat messaging apps
encryption techniques. The
using a technique based on researchers then used this
information flow analysis. information to simulate the key
generation processes, which
allowed them to access data from
the devices.
Through this project, the
A*STAR researchers team was able to assess the
have successfully recovered robustness of the chat-apps and
decryption keys for two suggest a variety of preventative
popular chat-apps — WeChat methods.
and WhatsApp. With these “Chat-app servers should
decryption keys, they could verify more than one piece of
potentially collect users’ personal information from an incoming
MOBILE data and private information. decryption key request
FORENSICS WeChat is particularly before releasing the key,” said
popular in Asia with more than Thing, “they should make an
700 million users and uses association between a device
an open-source library called phone number and the user
SQLCipher to encrypt data. By account, for example.” She
contrast, WhatsApp, owned points out, however; that their

BRIDGING by Facebook Inc., with more
than one billion active users
experiments were carried out
on exploitable devices with
THE SECURITY worldwide uses an encrypted escalated privilege. Even so,

DIVIDE FOR CHAT backup database file usually
stored on a device’s SD card.
she urges users to keep their
devices and applications ​
APPLICATIONS Vrizlynn Thing, who led updated to protect them
the project at the A*STAR from security risks.
Successful decrypting Institute for Infocomm
© Lujuan/EyeEm/Getty

demonstrations show that Research explained that many 1. Dai, Z., Sufatrio, Chua, T-W.,
Balakrishnan, D. K., & Thing, V. L. L.
chat-app designers should messaging apps use ‘end-to- Chat-app decryption key extraction
end’ encryption — only the through information flow analysis.
improve the ways they protect sender and receiver can read Cryptology and Information Security
users’ personal data messages and they are encrypted Series 15, 3–18 (2017).

24 A*STAR RESEARCH  Issue 10 | January – March 2018
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NEUROSCIENCE

WHAT A
HUNGRY FLY
CAN TELL US
ABOUT OBESITY
A*STAR researchers
have used brain cell
silencing technology
Understanding how to open new insights
into the role played by
a fly modulates its the brain in feeding
behavior.
feeding behavior could
help fight obesity

Turning various neural circuits “When we started this systems in genetically oxygen intake — which should
on and off in the brain of the project, I expected to find a lot of manipulated vinegar flies, have mirrored food intake —
vinegar fly could help A*STAR studies in this important area, but Drosophila melanogaster. actually decreased while food
researchers develop new was surprised to find just three “We used transgenes that intake increased.
treatments for obesity, diabetes, papers with five experiments. combine the fly’s own gene switch The group’s original
and heart disease1. Our study more than doubles with a protein that silences hypothesis was that
In changing external the available information.” electrical activity in neurons. disrupting neuromodulators
environments, animals, This way, we can shut off specific would have coordinated
including humans, maintain ‘‘We can shut modulator circuits and examine effects on feeding and other
a steady physiological energy off specific the effect this has on feeding.” aspects of physiology, but
state by altering both their modulator circuits The insects were then this was refuted — an outcome
internal metabolism and feeding assessed by monitoring that Claridge-Chang says
and examine the
behavior. If energy supplies 11 parameters: activity; could lead to important new
are low, for example, the brain
effect this has on climbing ability; individual insights. “The dissociation
produces hunger signals to
feeding.’’ feeding; group feeding; food of phenotypes implies that
drive food-seeking behavior to discovery; both fed and starved different modulatory circuits
replenish the animal’s reserves. “We wanted to know, if we respiration; fed and starved have disconnected or even
In a recent study, Adam turn off these different circuits, lipid content; and fed/starved oppositional effects on different
Claridge-Chang, and colleagues what will happen to the feeding body weight. physiological functions. We
© PLASTICBOYSTUDIO/Moment/Getty

from A*STAR’s Institute of behavior,” Claridge-Chang says. Claridge-Chang says the will test this hypothesis in
Molecular and Cell Biology “If we see a dramatic impact on results from these experiments future experiments.”
and the Singapore Institute of feeding, could that be a way of indicate that individual
Manufacturing Technology looked treating the compulsive eating neuromodulatory system effects 1. Eriksson, A., Raczkowska, M.,
Navawongse, R. Choudhury, D.,
at how inhibiting neuromodulator related to obesity?” on feeding behavior, motor
Stewart, J. C. et al. Neuromodulatory
cells that release dopamine and To find out, the activity and metabolism are circuit effects on Drosophila
serotonin would affect feeding and research team silenced five not related to each other. As an feeding behaviour and metabolism,
metabolic functions1. different neuromodulator example, in one experiment, Scientific Reports 7, 8839 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 25
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PRECISION
MACHINING

A microfluidic chip
injection mold.

A SMOOTHER
FINISH ALLOWS
FLUIDS TO FLOW
A magnetic method for
polishing metals enables
mold templates with
microscale features

Injection molding enables quickly create microfluidic to access the recessed
large-scale production of channels in polymer substrates. corners of microstructured
polymer and plastic materials “The technology addresses a surfaces and remove
with micrometer-sized features. critical problem in mold insert unwanted material uniformly.
Now, A*STAR scientists have fabrication for microfluidic chip Guo and his colleagues
developed a method for creating production, and will enhance started by milling their template
mold templates with high local industry,” says Guo. for a microfluidic channel 100
precision and few defects. micrometers in depth and width
A fluid behaves very The polish reduced on a special aluminum alloy. The
differently when it is confined to the roughness of the channel was 100 millimeters in
micrometer-scale channels. This length and included two fluid this magnetic polish. They
surface by a factor of
phenomenon already has several inlets, one fluid outlet and a observed that the process
four, leaving a mirror-
applications such as enabling the serpentine channel as reaction preserved the height of the
analysis of small samples of blood.
like finish. chamber. They then polished microstructure, although the
These microfluidic systems the template using a method edges were more rounded after
© 2018 A*STAR Singapore Institute of Manufacturing Technology

are small and portable, easy to Injection molding involves known as magnetic field-assisted polishing. The polish reduced
use without expert knowledge, shaping a material while in finishing. Two magnetic rollers the roughness of the surface by a
and disposable because they a molten state using a metal rotating in opposite directions factor of four, leaving a mirror-
are cheap to produce. But template. It is cheap, fast, and on either side of the mold create like finish. “The next step will
this disposability means that useful for creating microfluidic a magnetic field. This field be to use the polished mold
microfluidic chips need to be chips. However, engineering a controlled a magnetic abrasive template for actual injection
quickly mass produced. mold with precise micrometer- made of carbonyl iron powder molding,” says Guo.
Now, Jiang Guo and his scale features and smooth and alumina particles bound
colleagues from the A*STAR surfaces is challenging as burrs together by oil, which removed 1. Guo, J., Liu, K., Wang, Z. & Tnay, G. L.
Magnetic field-assisted finishing of a
Singapore Institute of and tool marks create defects. A any unwanted material and mold insert with curved microstruc-
Manufacturing Technology post-polishing process can fix smoothed the surface. tures for injection molding of micro-
have developed a method for some of these imperfections, but The researchers compared fluidic chips. Tribology International
fabricating molds that can it is difficult for polishing tools their template before and after 114, 306–314 (2017).

26 A*STAR RESEARCH  Issue 10 | January – March 2018
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it’s known that liver cells the cells’ defenses against HBV
contain factors that facilitate infection so that they can be
HBV replication, Ko and her used to test the efficacy of new
team found that the cells also drugs. “The reason for the very
VIROLOGY lack functional levels of the successful development of
proteins Slug and SOX7. These antiviral drugs for hepatitis C
proteins are found in most was the availability of robust,
other human tissues, where cell-based screening assays.
they bind to the HBV genome Hepatitis B has always been
and block the binding of the lacking in this area,” says Ren.
cells’ proteins that initiate and “When we introduce HBV into
HEPATITIS B promote viral replication. these Slug-deficient cell lines,

EXPLOITS THE “Slug and SOX7 are involved
in embryonic development
they show a large increase in
the viral load. This provides us
LIVER’S WEAKNESSES and that’s when they’re with a dramatically improved
most active,” says Ko. After platform to create a drug
In revealing the liver’s ‘weak spot’ for development, it is thought screening assay for HBV.”
hepatitis B virus replication, A*STAR that the proteins are no longer The SIgN team made
required in the liver, and so another unexpected discovery
scientists are paving the way for new
get ‘turned off.’ during their studies: human
drug development efforts colon, lung and stomach cells
“This provides also lack Slug and SOX7. The
us with a scientists are now collaborating
dramatically with clinicians at Singapore
In a surprising discovery, because HBV is very prevalent in improved General Hospital to launch a
researchers from the Singapore Asia,” says Ee Chee Ren, leader thorough investigation into
platform to
Immunology Network (SIgN), of the SIgN team that made the whether these tissues could
A*STAR, have found that the discovery.
create a drug act as a hidden reservoir of
liver is the main site of hepatitis “HBV enters the liver cells
screening assay HBV, potentially complicating
B (HBV) replication — not only through specific receptors for HBV.” disease treatment.
because it contains material that and then deposits its genetic
helps the virus proliferate, but material into the nucleus,” The team is now using 1. Ko, H. L., Lam, T. H., Ng, H., Toh, J.,
Wang, L. W. et al. Identification of
also because most other tissues explains SIgN’s Hui Ling Ko, tools including CRISPR-Cas9,
Slug and SOX7 as transcriptional
of the body contain proteins that the paper’s first author. The the pioneering gene editing
repressors binding to the hepatitis
actively repress HBV replication. viral DNA then hijacks the technology, to produce cells B virus core promoter. Journal of
“We’ve been working on this host cell’s machinery to make without any functioning Slug Hepatology 68, 42–52 (2017).
project for a number of years new copies of HBV. While or SOX7 proteins. This nullifies

In the absence of
protective proteins
Slug and SOX7,
hepatitis B infection
thrives in liver cells,
© 2018 A*STAR Singapore Immunology Network

indicated by green
staining in this
image.

www.research.a-star.edu.sg A*STAR RESEARCH 27
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Understanding how the immune expected, a type of white blood
system remembers allergy- cells called plasma cells in the
causing antigens could help recipient mice, which secreted
prevent severe reactions. IgG1 antigen-specific antibodies.
ALLERGY When a predisposed Surprisingly, however, they
person is initially exposed to also generated plasma cells that
an allergy-causing antigen, secreted IgE with a high affinity
specific antibodies, called for their specific antigen.
immunoglobulin E (IgE), are SP and DN IgG1 memory B
produced without leading to an cells also produced IgE-secreting
allergic reaction. If exposed to plasma cells. But the secreted IgE

CLINGING ON the allergen a second time, the
person may become ill. “But no-
had only a low affinity for their
antigens.
TO MEMORY one has found the memory IgE
cells believed to be responsible for ‘‘Knowing how
Immune cells hold their the illness,” says bioinformatics IgE memory is
memory of how to researcher and molecular viral generated, we
epidemiologist Michael Poidinger
respond to allergens in can ask questions
from A*STAR’s Singapore
a surprising way about drugs and
Immunology Network (SIgN).
Jin-Shu He and colleagues
preventative
at SIgN collaborated with treatments.’’
researchers in Singapore and
the US to decipher the function It remains unknown what
of IgE memory. Instead of causes the same double positive
finding IgE memory cells, they IgG1 memory B cells to generate
discovered that the memory cells IgG1 or IgE plasma cells. But the
of immunoglobulin G1 (IgG1), study reveals that IgG1 memory
another antibody, held the B cell subsets are important in

Reproduced from Ref. 1 and licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) © 2017 J. He et al.
memory of IgE responses. the memory of IgE responses.
The team injected mice with In a secondary allergic
one of two antigens, eliciting reaction, allergens bind to
a primary allergic immune IgE attached to the surface of
response. They then isolated a another type of white blood
type of immune cell from the cells, called mast cells, which
mice’s serum, called memory B then release chemicals to
cell, specific to IgG1. They found cause anaphylaxis. The team
three subsets of this memory hypothesize that low affinity IgE
B cell: double positive (DP), compete with high affinity IgE
single positive (SP) and double for space on the surface of mast
negative (DN) depending on cells, and may help limit severe
the types of receptors on their allergic reactions.
surface. These cells were then “This is an early phase
injected into mice that hadn’t study for this aspect of IgE
been previously exposed to and allergy,” says Poidinger.
the antigens; one of the two “Knowing how IgE memory is
antigens was administered, and generated, we can ask questions
a secondary allergic immune about drugs and preventative
response occurred. treatments.”
The researchers found that
Previously unexposed mice were first injected in their right ears with DP IgG1 memory B cells from 1. He, J. Subramaniam, S., Narang, V.,
DP or DN IgG1 B cells and then they were intravenously injected with an Srinivasan, K., Saudners, S. P. et
the donor mice — those that
antigen. Those injected with DP, on the left, showed a local anaphylactic al. IgG1 memory B cells keep the
reaction in their ear (blue). Those injected with DN, on the right, did not. held the memory for either of memory of IgE responses. Nature
This demonstrates that only the DP cells are producing high affinity IgE. the two antigens — produced, as Communications 8, 641 (2017).

28 A*STAR RESEARCH  Issue 10 | January – March 2018
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CANCER
GENETICS

CLASSIFY
AND
CONQUER
Molecular dissection of
bile duct cancer reveals A schematic of the di-
gestive system including
subtypes with different the stomach (orange),
origins and varying liver (brown), gallbladder
(green), and the bile duct
potential treatments (green tubes).

Researchers have discovered that the team investigated the Centre Singapore, one of the in the methylation patterns
cholangiocarcinoma (CCA), a genomic sequences of the tumors study’s senior authors. offer clues about the processes
form of liver cancer also known as and their epigenomic and gene One of the clusters was acting in each cluster. “Based on
bile duct cancer, consists of several expression profiles. They divided characterized by changes in molecular data, we can speculate
molecular subtypes with distinct the cancers into four groups with genes associated with immune about the different mechanisms
potential therapies and prognoses. different patterns of mutations response, suggesting that leading to different DNA changes
An international and other genetic defects, two it might be a candidate for in the development of CCA. You
collaboration led by Patrick of which were associated with immunotherapy treatment. really can’t see that from just the
Tan of A*STAR’s Biomedical liver-fluke infection. “The Likewise, the characteristics of anatomical information,” says
Research Council, analyzed current way of classifying CCAs some of the tumors indicated that co-lead author Chern Han Yong.
tumors collected from almost is by their anatomical subtype. they might respond to therapeutic These findings demonstrate
500 bile duct cancer patients Our data shows that if you look interventions currently in use that distinct molecular subtypes
in 10 countries, in a study that at molecular data, you get more or under development. “We’ve can result from different
is part of the International clinically relevant subtypes that shown that about a third of the cancer triggers. Learning
Cancer Genome Consortium. have different potential therapies patients can be treated using more about these subtypes and
By examining a large, diverse and prognoses,” says Bin Tean existing therapies, if experimental how they link with various
group, the researchers were able Teh of the National Cancer drugs were included it would carcinogenic processes may
to uncover patterns missed in be even more”, says lead author, reveal the mechanisms behind
earlier investigations, such as Apinya Jusakul. Currently, these cancers and guide the
‘‘About a third
one that included only North surgery is the only treatment for development of therapeutic
American patients, all of whom
of patients can bile duct cancer. interventions.
were free of the liver-fluke be treated using The molecular clusters
© Stocktrek Images/Getty

infection that is a common existing therapies, can also guide researchers in 1. Jusakul, A., Cutcutache, I., Yong, C. H.,

catalyst for bile duct cancer in if experimental understanding the development
Lim, Y. Q., Huang, M. N. et al. Whole-
genome and epigenomic landscapes
Southeast Asian patients. drugs were of CCA. Two of the clusters of etiologically distinct subtypes
Using modern high- included it would had an excess of methylation, a of cholangiocarcinoma. Cancer
throughput DNA sequencing, be even more.’’ DNA modification. Differences Discovery 7, 1116–1135 (2017).

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30 A*STAR RESEARCH  Issue 10 | January – March 2018
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By visually inspecting the
ENF, human investigators
can reliably match recorded
fluctuations to a time in the
AUDIO long-term records, but this is
FORENSICS
a laborious task best done by a
computer. In response, the I2R
team developed a similarity
criterion called bitwise similarity
(bSim) that mimics the way
humans judge the similarity of
two signals.
The team tested bSim by
FREQUENCY using it to identify the timing
FINGERPRINTS INCREASE of 187 audio recordings made
around Singapore using various
CRIME-FIGHTING POWER mobile phones.
They found that bSim
A system that recognizes electrical greatly outperformed previous
power grid fluctuations hidden in audio similarity metrics, which were
thrown into doubt by small
recordings provides a powerful forensic
deviations even when the general
tool for police investigators shapes of the signals were
clearly similar. “bSim enables
us to focus our attention on the
overlapped parts instead of being
Audio and video recordings which provides each recording drawn away by the deviated
are important sources with a unique fingerprint parts,” says Zheng.
of evidence in criminal that can be compared to the “The science behind ENF
investigations, especially as long-term records captured pattern matching has been
more electronic devices are continuously and maintained proven to be reliable, like
in use now than ever before. at forensic labs. fingerprints and DNA,” says
However, for recordings to Thing. “It has been used in
be admissible, investigators “The science courts in various jurisdictions
often need to determine the behind electrical and the cases cut across many
time they were made, which network different crimes. We hope to
can be difficult. Now, a frequency pattern extend our work from audio
team led by Vrizlynn Thing recordings to videos, which
matching has
at the A*STAR Institute for not only contain audio but may
been proven to
Infocomm Research (I2R), in also enable us to ‘see’ the ENF
collaboration with the Singapore
be reliable, like through variations in lighting.”
Police Force, has developed fingerprints and “This innovative solution
a new system that reliably DNA.” towards audio authenticity
estimates the time of recordings verification developed by I2R
by identifying small fluctuations “The random fluctuations has already proven itself in
in the frequency of the electrical are consistent across different actual use, and we are excited
The frequency of the power grid. places within the same about the potential it holds,”
electrical power grid fluc- The ‘electrical network power grid,” explains team says a statement from the
tuates randomly over time,
© hugociss/Moment/Getty

frequency’ (ENF) of power member Lilei Zheng. “As Singapore Police Force.
leaving unique fingerprints
in audio files that can help
grids is centered around 50 a consequence, recordings
© xxxxxxxxxxxxxx

or 60 Hertz, and is picked captured in different places at 1. Zheng, L., Zhang, Y., Lee, C. E. & Thing,
investigators identify the
V. L. L. Time-of-recording estimation
time of recording. up in audio recordings as a the same time will have ENF for audio recordings. Digital
background hum. The ENF fingerprints showing the Investigation 22, S115-S126 (2017).
shifts up and down randomly, same fluctuations.”

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NEUROSCIENCE

DIVERTING
DISTRACTION
To avoid getting sidetracked
by distractions, neurons in the
brain’s short-term memory center
Electrical signals in the brain’s short-term memory center (as shown above), located in
reorganize their activity patterns the prefrontal cortex, morph when faced with distracting stimuli.

The ability to remember schizophrenia and dementia, were shown a grid on a screen This was not the case in
something like a grocery list or all of which involve memory and trained to remember the the frontal eye field, however.
telephone number even under deficits. location of a red square that There was no evidence of
bombardment from loud noises, The brain’s center for flashed briefly, without getting code-morphing ability in this
incoming text messages or other short-term memory storage sits thrown off by the subsequent visual part of the brain. This
distractions requires an intricate behind the forehead in the lateral flash of a green square. told the researchers that there
shape-shifting act in the brain. prefrontal cortex. The neurons Each monkey had a suite was something special about
A Singaporean team has there were once thought to be of electrodes implanted in the short-term memory retention
found that the neuronal response unaffected by disruptions, but brain, both in the prefrontal in the prefrontal cortex. They
patterns responsible for retaining Libedinsky’s team has shown cortex and in the frontal eye traced this cognitive capacity to
short-term memories reorganize otherwise. field, a nearby region involved a unique set of neurons with the
into a different configuration in in controlling visual attention ability to multitask.
the face of distracting stimuli There is and eye movements. This “These results will be
— a process dubbed ‘code- something allowed the researchers to track of interest to researchers
morphing’. special about neuronal activity as the monkeys in a number of fields,” says
“This code-morphing short-term performed the memory test. Aishwarya Parthasarathy, a
capability may be an important The team found that neurons postdoctoral research fellow at
memory
factor underlying cognitive in the prefrontal cortex became A-STAR and the study’s first
flexibility,” says Camilo
retention in activated following the initial author, noting that all areas of
the prefrontal
© 2018 A*STAR Institute of Molecular and Cell Biology

Libedinsky, a neuroscientist stimulus, maintaining the memory-related research —
at the A*STAR Institute of cortex. memory of the location, but this cognitive neuroscience, artificial
Molecular and Cell Biology who activity — the ‘code’ used by intelligence and neuropsychiatry
co-led the research. Working with Shih-Cheng the brain to remember the red — could benefit from the
The team’s findings may Yen, an electrical engineer square’s location — morphed discovery.
help computer scientists at the National University of after the monkeys saw the green
develop more brain-like neural Singapore, Libedinsky and square, creating a different 1. Parthasarathy, A., Herikstad, R.,
Bong, J. H., Medina, F. S., Libedinsky,
network algorithms for artificial colleagues trained two long- code held by the same group of C. & Yen, S. C. Mixed selectivity
intelligence, or help biomedical tailed macaques to perform a neurons, all without losing any morphs population codes in prefron-
researchers better understand simple visual task. Using drops information or impacting the tal cortex. Nature Neuroscience 20,
diseases such as Parkinson’s, of juice as a reward, the monkeys memory in any way. 1770–1779 (2017).

32 A*STAR RESEARCH  Issue 10 | January – March 2018
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Isolated, growing human hair
follicle, showing mitochondrial
membrane potential (red) and
reactive oxygen species (green).
MEDICAL
BIOLOGY

GETTING TO
THE ROOT OF
HAIR LOSS
The age-old search for
a cure for hair loss may
be close to an end

Understanding the energy In particular Dawson’s hair — only a small change in The team also uncovered a
it takes to grow a strand of hair team is examining the role that metabolism makes a noticeable previously unknown region in
could hold the key to ensuring mitochondrial metabolism and difference.” the hair shaft which they called
women, in particular, end their its by-product, reactive oxygen, Hair growth is an energy- the ‘ring of fire’ because it is a
lives with a wonderful bouffant. play in the bioenergetics of the intensive process, Dawson says, major source of reactive oxygen
Recent research by A*STAR hair follicle. with an average human growing species.
scientist Thomas Dawson and almost two meters of hair over Dawson says this study
his team, in collaboration with their body per hour. shows that hair follicles and
“People who
researchers from the Medical “It takes about 670 kilojoules growth are more complex
University of South Carolina
go on crash of energy to grow one gram of than previously thought, and
Pharmacy School Department diets, students hair, which is the equivalent of that quelling the formation of
of Drug Discovery, suggests that undertaking six minutes of intense exercise reactive oxygen species and
the slowing of the metabolism exams, all will using both arms and legs,” maintaining mitochondrial
as we age could be a driver of lose hair — only Dawson points out. metabolism could be key to
‘chronogenetic alopecia’ or age- a small change He believes the cells that improving hair quality as we age.
related hair loss, a condition that in metabolism create the hair multiply and “If we use materials such
predominantly affects women. makes a synthesize biomass so quickly as leave-on creams or lotions
Dawson, from A*STAR’s noticeable that they burn enormous that alter metabolism you can
Institute of Medical Biology, says difference.” amounts of energy much like change the way hair grows and
that the majority of hair research “driving a car with both feet make follicles survive longer and
© 2018 A*STAR Institute of Medical Biology

to date has focused on balding down hard on the gas”. produce better hair.”
men — even medical books “As we age mitochondrial “The motor is running
from Cleopatra’s reign contained energy production slows, so we absolutely flat out and as a 1. Lemasters, J, Ramshesh, V. K.,
Lovelace, G. L., Lim, J., Wright, G.
formulas to cure hair loss. end up with a reduced ability to result there is excess reactive D., Harland, D. & Dawson, T. L. Jr.
His latest study uses cutting- make good hair,” he says. “Any oxygen generation in the hair Compartmentation of mitochondrial
edge laser microscopy on plucked time there is a screw up in your follicle that actually damages the and oxidative metabolism in growing
human and bovine hair to better metabolism you lose hair. People structure. The follicle then loses hair follicles: A ring of fire. Journal
of Investigative Dermatology 137,
understand hair growth at a who go on crash diets, students its ability to continue to operate 1434–1444 (2017).
molecular and metabolic level. undertaking exams, all will lose at full form over time.”

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a 10μm
1 3

2 4
PHOTONICS
b

TE, 1520nm
A SIMPLER PATH
A fresh design approach greatly
simplifies a key component of TE, 1570nm
photonic circuits by optimizing
the coupling of straight and
curved light paths
TE, 1620nm
An electron micrograph of the fabricated coupler (a), and -10 -5 0 5 10
the optical energy in the two waveguides (b). μm

A core element of circuits A broadband “However, it has been very Ong’s team came up with
handling optical signals can now coupler that difficult to try to make them a design methodology based

Modified from Ref. 1 and licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) © 2017 G. Chen et al.
be made smaller and simpler, and provides reliable compact, with low power loss on a mathematical ‘transfer
with functionality over a wider performance over and broadband operability, using matrix method’ to determine the
range of wavelengths, because of a wide range of standard processes.” coupler section lengths, radii,
a mathematical model developed useful wavelengths A coupler works by running and waveguide cross-sections
by A*STAR researchers1. The a second optical path, known that would give the desired
is something
new design methodology is as a waveguide, alongside the operation with low wavelength
expected to have widespread use
of a holy grail signal path. The optical signal sensitivity. Using this approach,
in photonic integrated circuits
for photonics induces a secondary signal in the the team designed and fabricated
and contribute to more compact engineers. adjacent waveguide, passing with a 50/50 power splitter with a
photonic devices. it some of the signal’s energy. wide bandwidth and length of
Optical signals, such as To overcome this obstacle to However, the ratio of power just 20 micrometers.
those transmitted over optical photonic circuit miniaturization, splitting changes depending on “We were able to improve
fiber, require photonic elements Jun Rong Ong and colleagues the wavelength of the signal, so a the broadband performance
and circuits to be useful. One from the A*STAR Institute of broadband coupler that provides of the photonic power splitter
of the most important photonic High Performance Computing, reliable performance over a wide through a simple modification
functions is ‘coupling’, which in collaboration with researchers range of useful wavelengths is of existing designs, and have
allows the signal to be split into from the Singapore University something of a holy grail for achieved a balanced 50/50
two different paths or used to of Technology and Design, went photonics engineers. output which is difficult by
drive other dependent circuits. back to the drawing board to find “We distilled the key other designs,” Ong says.
Coupling, however, is generally a simpler approach to designing ingredient that makes a
only reliable over a narrow these critical coupling elements directional coupler a broadband 1. Chen, G., Ong, J.R., Ang, T.Y.L., Lim,
S.T., Png, C.E., & Tan, D.T.H. Broadband
band of wavelengths, for broadband operation. splitter – a combination of silicon-on-insulator directional cou-
demanding a complicated “Couplers are the basic straight and bent waveguides plers using a combination of straight
design and fabrication process building blocks of photonic – and thoroughly explored and and curved waveguide sections.
and bulkier circuits. circuits,” explains Ong. exploited it,” says Ong. Scientific Reports 7, 7246 (2017).

34 A*STAR RESEARCH  Issue 10 | January – March 2018
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The researchers alpha during inflammation.
discovered that not only They tested this by
do dendritic cells exist as co-culturing adult and
early as 12 weeks gestation, fetal dendritic cells with
IMMUNOLOGY but, when stimulated by T cells, and showed that
molecules that interact with only the adult dendritic
the toll-like receptors found cells triggered production
on the surface of the cells, of large amounts of TNF-
mimicking the interaction alpha from the T cells,
with a bacterial or viral while fetal dendritic cells
attack, they behave almost inhibited it through release of
exactly the same as adult arginase-2.
FETAL IMMUNE cells. The results could help our
SYSTEM DEVELOPED, “We found that the cells
in the tissue were able to
understanding of pregnancy
conditions such as pre-
BUT TOLERANT migrate to the lymph nodes eclampsia and gestational
very early, which means they diabetes, which Ginhoux
More mysteries of the developing were able to talk to T cells, suggests could be the result
immune system have been revealed so everything looks similar of a disruption in this careful
in a study of fetal dendritic cells to what we find in adults,” balance of immune activation
Ginhoux says. and tolerance in the fetus.
But this posed further
questions: if a fetal immune 1. McGovern, N., Shin, A., Low, G.,
Low, D., Duan, K. et al. Human
system responded to threats fetal dendritic cells promote
The fetal immune system and Children’s Hospital, in exactly the same way as prenatal T-cell immune
is fully developed and Singapore. an adult immune system, the suppression through arginase-2.
functional from as early Ginhoux and co-authors resulting inflammation could Nature 546, 662-666 (2017).

as 16 weeks gestation, but analyzed fetal tissues — theoretically cause harm to
has a mechanism to keep it donated under strict ethical the developing fetus.
suppressed until after birth, guidelines — for dendritic The research team
according to an A*STAR- cells, which are immune cells compared genes from fetal
led study. Their findings that sample the environment and adult dendritic cells, and
Licenced under CC-BY (https://creativecommons.org/licenses/by/4.0/), Dr Benoit Malleret, SIgN.

could shed light on the for potential threats and pass found one very significant
immunological mechanisms that information to the T cells difference; fetal dendritic
underlying fetal-maternal and B cells to ward off those cells over-express an enzyme
health problems such as pre- threats. called arginase-2,
eclampsia. which is known
“People thought that to block the T
“People thought
the fetal immune system cell secretion
was defective because it
that the fetal of a key
was not mature, but we’ve immune system inflammatory
discovered that it’s highly was defective signaling
dynamic, highly functional, because it was not molecule
and in fact represents another mature, but we’ve called TNF-
specialization,” says Florent discovered that it’s
Ginhoux, from the Singapore highly dynamic,
Immunology Network at functional and
A*STAR, who co-led the represents another
study with Jerry Kok Yen specialization.”
Chan from the KK Women’s

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A cell produces RNA by that converts the nucleotide
copying stretches of its DNA, adenosine to inosine, the most
and then RNA is subjected to common kind of RNA editing in
various kinds of processing animals.
GENOMICS which gives rise to some of the The results revealed several
variability observed between surprises. For a start, the greatest
different types of cells. It also amount of editing of RNA that
goes some of the way toward codes for proteins was found
explaining the complexity of to occur in the arteries, and
humans despite the fact that not in the brain, as previously
we do not have vastly more thought. Also, the comparison

MAPPING protein-coding genes than other
mammals.
between species revealed that
RNA editing profiles are more
RNA EDITING “RNA editing diversifies similar between different organs
the transcriptome,” explains in a single species than they
A large-scale study explores Meng How Tan of the A*STAR are between the same organ in
how RNA editing varies Genome Institute of Singapore. different species.
“If every variation of a transcript The team is now exploring
between different tissue
was genetically encoded, our how diseases occur when RNA
types and primates genome would be enormous.” editing goes wrong. “There
By drawing on the resources are over a million editing sites
of the Genotype-Tissue in humans, but for the most
Expression (GTEx) Consortium, part, no-one knows what their
In a large-scale study of more and cell types are important in Tan and his colleagues have functions are,” says Tan. “We are
than 8,500 human samples various diseases. conducted a survey of RNA now actively investigating how
and hundreds of primate Almost every cell in your editing in more than 8,500 RNA editing is dysregulated in
and mouse samples, A*STAR body contains nearly identical human samples (corresponding various diseases, and we have
researchers have investigated copies of your DNA, which is to 53 tissue types in 552 ongoing collaborations with
how RNA editing allows for the why DNA profiling is so useful individuals). They also analyzed clinicians in Singapore.”
variable expression of genes in in forensic analysis. But how hundreds of samples from the
different human organs, and that DNA is expressed varies mouse and four other primates: 1. Tan, M. H., Li, Q. Shanmugam, R.,
Piskol, R., Kohler, J. et al. Dynamic
those of other mammals1. The greatly in different kinds of cells, chimpanzee, macaque, baboon landscape and regulation of RNA
mammalian atlas will help resulting in the diversity of body and marmoset. The team focused editing in mammals. Nature 550,
scientists determine what genes tissues. on the RNA editing process 294–254 (2017).

RNA being edited
by an enzyme.
The enzyme
ADAR1 (green and
gold) converts
adenosine
into inosine
in the genetic
sequence.
© LAGUNA DESIGN/SCIENCE PHOTO LIBRARY

36 A*STAR RESEARCH  Issue 10 | January – March 2018
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ESCAPING SILICON
SEMICONDUCTOR An alternative fabrication scheme for microscale
LASERS
semiconductor lasers could expand the applications
of on-chip lasers beyond conventional silicon

A systematic study of a simple “We needed to
and general structure for on-chip
develop a generic
semiconductor lasers by A*STAR
integration
researchers sets the scene for
much broader application of
scheme that
integrated semiconductor lasers would allow
beyond conventional silicon- us to fabricate
based systems1. laser devices
The ability to use, manipulate on different
and sense light is applicable substrates, not
to many technologies, from just silicon.”
data interconnection and fiber
optics to optical sensors and
optical storage systems. Tiny types of reflectors without
lasers are routinely integrated additional processing steps. The
into microchips for these team then used this fabrication
‘optoelectronics’ applications scheme to test facet reflectors
using a well-understood silicon- made by depositing a thin gold
based laser structure, but film, by chemical modification of
alternative and potentially simpler the surface, or by etching an air
structures in non-silicon systems gap (see image).
have yet to be explored in detail. Studies of the different
One such non-silicon-based laser structures fabricated in
application is a new type of data the A*STAR laboratory and
An etched facet semiconductor laser with an air gap reflector.
storage system called heat- supporting simulations revealed
assisted magnetic recording that a thin gold layer, less than
(HAMR), which researchers producing the laser light. current into a light emission. 100 nm thick, afforded the best
Reprinted with permission from Ref 1, Optical Society of America.

at the A*STAR Data Storage “We needed to develop a They do this by taking light performance in terms of facet
Institute have been working generic integration scheme that produced by a stack of ultrathin reflectivity, minimum lasing
on as a next-generation data would allow us to fabricate laser layers of a light-emitting current, emission efficiency and
storage technology. HAMR devices on different substrates, semiconductor (in this case output power.
uses integrated lasers for fast not just silicon,” says Lee. “For aluminum-gallium-indium- “We expect our results to
and precise micro-spot heating this, a facet reflector structure arsenide), and multiplying light serve as benchmark for research
of a magnetic medium, but is very useful, but low facet at the target wavelength using a and development on etched facet
requires the laser to be formed reflectivity is a problem, and resonant cavity formed between lasers with different reflectors,”
on aluminum-titanium-carbide using different reflectors usually two reflectors. says Lee.
(AlTiC) rather than silicon. This means a more complicated By designing a faceted laser
presented Chee-Wei Lee and fabrication process and greater structure considering process 1. Lee, C.-W., Ng, D. K.-T., Ren, M. Fu,
Y.-H., Kay, A. Y. S. et al. Comparison
his colleagues with a significant chance of device failure.” integration, Lee and his team of III-V/Si on-chip lasers with etched
problem, since the silicon The lasers used in such developed a fabrication scheme facet reflectors. Applied Optics 56,
substrate plays in integral role in applications turn electrical that can accommodate different 5086–5091 (2017).

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Computer-generated imagery of an
abnormal growth in the colon. A*STAR
scientists have now provided compelling
evidence that metformin might be
a useful clinical agent to treat such
© xxxxxxxxxxxxxx

life-threatening malignancies.

38 A*STAR RESEARCH  Issue 10 | January – March 2018
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demonstrate response using
therapeutic doses of the drug:
“We tested a wide range of
concentrations down to the
COLORECTAL physiological,” says Tan. “It
CANCER was important to show that
there was a response at that
level, as many studies have not
documented that.”

“Our study shows
MORE EVIDENCE that metformin has
FOR METFORMIN a possible activity
against colorectal
A popular diabetes drug could cancer.”
one day be used to treat
The IBN-led collaboration
malignant tumors
discovered that metformin
enacted its therapeutic benefits
by activating a cellular pathway
implicated in the inhibition of
A*STAR researchers have The team took samples of cancer, and by reducing cancer
provided strong evidence, cancer tissue from two patients cell oxygen consumption.
using patient tumor grafts, that and implanted them in mice, Using next-generation genetic
metformin, a common diabetes then assessed how the tumors sequencing, the team also
drug, might help fight colorectal responded to metformin as provided evidence that direct
cancer in humans. well as 5-fluorouracil, the patient tissue grafts in mice
Metformin’s potential as current front-line treatment for retain the genetic, molecular,
a tumor-suppressing agent, to colorectal cancer. and tissue features of the original
prevent the growth of breast, They found that metformin tumor — making them ideal
colon, lung and prostate cancers, inhibited tumor growth by at platforms to study colorectal
has been demonstrated in least 50 per cent after 24 days cancer and its treatment.
pre-clinical studies. However, and, when combined with It’s believed that this is
the experimental models 5-fluorouracil, inhibited the the first investigation into
used in these studies do not tumor grafts from one patient metformin and colorectal cancer
accurately recreate the natural by 85 per cent. The experiments using patient tumor grafts.
manifestations of the disease, used concentrations of Tan says that future studies
and require toxic levels of metformin equivalent to that could shed light on metformin’s
metformin to demonstrate used to treat diabetes in humans. relevance as a therapeutic agent
beneficial effects. In previous studies, for cancer: “Our study shows
Min-Han Tan and a group scientists typically injected that metformin has a possible
of researchers from A*STAR’s cancer cells into host animals activity against colorectal cancer,
Institute of Bioengineering and rather than transplanting using gold-standard materials,
Nanotechnology (IBN), the tissue directly. In these models, and provides a mechanism to
© Juan Gaertner/Science Photo Library/Getty

Biological Resource Centre, high glucose, insulin, and explain this. Further clinical
and the Genome Institute of growth factor levels are needed trials are now needed.”
Singapore, with collaborators to establish cell cultures for
from hospitals across Singapore, injection. Tan’s group suspects 1. Suhaimi, N-A. M., Phyo, W. M.,
Yap, H. Y., Choy, S. H. Y., Wei, X.
have now tested metformin’s that this artificial environment
et al. Metformin inhibits cellular
cancer-fighting abilities on a meant previous studies needed
proliferation and bioenergetics in
model of colorectal cancer that higher levels of metformin colorectal cancer patient-derived
is more representative of how the to stunt tumor growth as, in xenografts. Molecular Cancer
disease appears in humans. this study, they were able to Therapeutics 16, 2035–2044 (2017).

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HORMONE DISCOVERY OPENS PATH
PREGNANCY
FOR NEW PRE-ECLAMPSIA TREATMENT
Early diagnosis and treatment of pre-eclampsia could soon be
possible due to the discovery of the pregnancy hormone ELABELA

A hormone secreted by the
placenta during pregnancy
may play a key role in the
development of pre-eclampsia;
a major worldwide cause of
maternal and fetal death.
A*STAR researchers first
discovered the hormone, called
ELABELA, or ELA, in 2013
and showed, in zebrafish, that
it was essential for normal
embryonic development of
the heart and cardiovascular
system. Further work revealed
that, in mammals, ELA was
produced by the placenta, and
when administered to rats
and mice, caused their blood
pressure to drop.
“So if you consider the
two — a hormone specifically ‘‘We have uncovered However, Reversade says the which affects 5–8 per cent of
expressed in the placenta, that a completely new most exciting discovery of the all pregnancies.
has blood pressure-lowering signaling pathway, research was that treating the “One of the biggest unmet
properties — one would expect a hormone and its pregnant knockout female mice needs in the field is that we don’t
that its absence would trigger receptor, in the with ELA hormone reversed have early predictive diagnostic
gestational hypertension, a key their pre-eclampsia symptoms biomarkers of when a woman
pathogenesis of
symptom of pre-eclampsia,” and increased the birth weight of is susceptible to develop pre-
says Bruno Reversade, research
pre-eclampsia.’’ their offspring. eclampsia,” Reversade says.
director at the A*STAR Institute “We have uncovered a Researchers are now
of Medical Biology. inability to produce ELA, the completely new signaling examining this hormone in
In this new international other half did survive. pathway, a hormone and its humans, starting with a study
study led by A*STAR, But when the female receptor, in the pathogenesis comparing ELA levels in
researchers crossed male knockout mice grew to of pre-eclampsia. Because it’s a pregnant women with pre-
© Caiaimage/Agnieszka Wozniak/Getty

and female mice that each adulthood and became hormone, it could be developed eclampsia and those with normal
carried only one copy of the pregnant, they showed high into a drug as is insulin for blood pressure.
ELA-coding gene to produce blood pressure and protein in diabetes,” Reversade says.
‘knockout’ mice. Around half their urine, classic signs of pre- This discovery also opens up 1. Ho, L., van Dijk, M., Tan Jian Chye, S.,
Messerschmidt, D. M., Chng, S. C. et
of these knockout mice showed eclampsia, while their fetuses the possibility of using ELA, or al. ELABELA deficiency promotes
severe embryonic cardiovascular also had the lower birth weight more specifically the observation pre-eclampsia and cardiovascular
malformations and did not typical of babies born to of lower ELA levels, to enable malformations in mice. Science 357,
survive to birth. Despite their mothers with the condition. early diagnosis of pre-eclampsia, 707–713 (2017) .

40 A*STAR RESEARCH  Issue 10 | January – March 2018
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NANOPARTICLES

LET LIQUID FINGERS
POINT THE WAY
Tiny gold spheres can be
manipulated on surfaces with
nanometer precision using the
effects of solvent evaporation A scanning electron micrograph of 8 nanometre-sized gold nanoparticles on a triangular template.

Unlocking the molecule- the nanoparticles inside the in positioning. For example, equilateral to right-angled
detecting capabilities of templates pushing them to their elongated liquid ‘fingers’ triangles revealed the potential
gold nanoparticles often target locations. within square templates forced of asymmetrical patterns — up
requires positioning techniques Mohamed Asbahi from the nanoparticles to move to to three nanoparticles could
that are beyond the limits of Institute of Materials Research corners where the solvent be trapped and positioned at
conventional lithography. and Engineering at A*STAR volume is the largest. various nanoscale separations in
An A*STAR team now recalls trying to control self- right-angled templates.
demonstrates that a combination assembly within square-shaped “We were Further experiments
of topographical templates templates when he and his surprised by this demonstrated that particular
and localized traps left by co-workers made an intriguing liquids can have different
effect before we
evaporating liquids can fabricate discovery. “We were increasing impacts on nanoscale patterns.
understood the
arrays of nanoparticles with cavity sizes in the templates, While toluene tends to ‘pin’
controllable separations below and expected to see more
physics behind it.” to the template structure and
five nanometers1. nanoparticles inside trying to trap nanoparticles at lower-
Left alone, nanoparticles optimize their arrangement,” “We were surprised by than-normal densities, hexane
tend to agglomerate due to he says. “But with toluene as the this effect before we understood solvents produce fully-packed
their high entropy. Because solvent, only four nanoparticles the physics behind it,” says surfaces. Asbahi notes that
© 2018 A*STAR Institute of Materials Research and Engineering

keeping gold nanospheres set were trapped at each corner of Asbahi. “But after we predicted the control offered by this
distances apart is critical for a square — no matter how large irregular cavities were technique could be sufficient
applications, including optical the cavity.” more successful at directing for integration into prefabricated
bioimaging, researchers are To explain this behavior, nanoparticles than equilateral circuits and plasmonic
developing ways to fabricate the researchers developed ones, we chose to validate nanostructures.
hundreds of thousands of these a virtual model to simulate our explanations with
objects automatically. One interactions between the triangular templates.” 1. Asbahi, M., Dong, Z., Wang, F.,
Saifullah, M. S. M., Yang, J. K. W. &
promising route, known as deposited nanoparticles and Working with state- Chong, K. S. L. Second order
directed self-assembly, deposits solvent within confined cavities. of-the-art electron beam directed positioning of nanoparticles
liquid suspensions of reagents These computations showed that lithography, the researchers induced by the main terminal
on to substrates with predefined after the liquid begins drying fabricated templates containing meniscus shape in irregular
template cavities. Nanoscale 9,
small-scale patterns. Liquid out, the shape of the retreating thousands of triangles just a few 9886–9882 (2017).
capillary action then draws interface played a key role nanometers in scale. Comparing

www.research.a-star.edu.sg A*STAR RESEARCH 41
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A single molecule of water is the the National Supercomputing
reason certain mutations are more Centre, Singapore, showed that
responsive to a ‘targeted’ cancer this deletion creates a more
therapy, according to molecular- physically constrained structure,
ONCOLOGY scale simulations carried out at the which can snugly accommodate
A*STAR Bioinformatics Institute. both afatanib and a single
Targeted therapies that take water molecule in a very stable
down tumors by selectively arrangement. In contrast, the
interfering with the defective mutant EGFR L858R, also found
proteins that promote their to characterize lung cancer,
survival and growth have contains just a single amino acid
ALL IN A MOLECULE OF revolutionized cancer therapy. substitution, and is predicted

WATER FOR EFFECTIVE
For example, the drug afatanib to hold two water molecules in
is a targeted agent given to lung its pocket. However, these are
CANCER THERAPY cancer patients with certain
mutations in the gene encoding
in a weaker and relatively less
stable arrangement, resulting
Molecular simulations reveal why certain the epidermal growth factor in weakened interactions with
receptor (EGFR). Recent clinical afatanib that likely reduce
cancer therapeutics may bind — or fail
studies suggest that afatanib may the drug’s affinity and hence
to bind — to mutant proteins confer survival benefit specifically effectiveness.
in patients with the EGFR19del “Our hypothesis is based
mutation rather than in patients on understanding the physics
with a different mutation, known of the system and could offer
as EGFR L858R, when compared with a compelling rationale for
patients receiving only standard the clinical observations
chemotherapy. with afatanib,” says Kannan.
Daniel Shao-Weng Tan, Intriguingly, he and Verma were
a clinical oncologist from also able to home in on other
A*STAR’s Genome Institute binding pocket mutations (single
of Singapore and the National nucleotide polymorphisms, or
Cancer Center of Singapore, who ‘SNPs’) that occur alongside
participated in these trials in EGFR19del that might likewise
Singapore, was confounded by influence the efficacy of afatanib.
this disparity, so he consulted The researchers are now
scientist Chandra Verma at examining whether these
the Bioinformatics Institute to predictions hold in real-life
rationalize their findings. Verma experiments and see this as a
and Srinivasaraghavan Kannan, a promising general strategy for
specialist in molecular modeling predicting patient response to
at the Bioinformatics Institute, targeted treatments. “We are
teamed up with Tan to identify trying to develop a robust pipeline
differences in the structure and to examine the structural effects of
dynamic behavior of these two mutations on drug interactions,”
mutant proteins that might Kannan says. “This will be a very
explain the distinct response valuable approach to complement
profiles. our engagement with the national
© 2018 A*STAR Bioinformatics Institute

It turns out that the critical precision medicine efforts.”
difference was a mere molecule
of water. Afatanib binds to a 1. Kanna, S., Pradhan, M. R., Tiwari,
G., Tan, W.-C., Chowbay, B. et al.
pocket on EGFR that is missing
Hydration effects on the efficacy of
five amino acids in the EGFR19del
Molecular simulation of afatinib (magenta) bound to EGFR 19del (gray), with the epidermal growth factor receptor
a single water molecule (red sphere) mediating interactions (dotted line) mutant. Molecular dynamics kinase inhibitor afatinib. Scientific
between the drug and the protein. Other mutation-prone amino acids within simulations carried out at the Reports 7, 1540 (2017).
the drug-binding pocket are individually colored. Bioinformatics Institute and

42 A*STAR RESEARCH  Issue 10 | January – March 2018
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FASTER DATA TRANSFER
PHOTONIC
THROUGH PLASMONS
DEVICES A transducer that converts electrical signals directly
into surface plasmons could allow rapid data transfer
and link photonic devices to electronics

Photonic and electronic devices insulating ‘quantum tunneling’
could soon be successfully barrier. Electrons that make the
integrated thanks to new quantum leap across this gap
transducers developed by a will either generate or detect
team of Singaporean researchers SPPs.
that can generate, manipulate By joining two transducers
and read small packets of with a plasmonic waveguide, so
energy called surface plasmon that one acted as a source and
polaritons (SPPs). another as detector (see image),
Photonic devices, which use the researchers observed about
light rather than electric charges 1 in 7 of the tunneling electrons
to carry information, can coupling to a SPP. Although the
operate thousands of times faster reasons for this high tunneling
than conventional electronics, rate are uncertain, Chu and co-
although they tend to be large workers suggest that SPPs
and difficult to integrate with at the junctions might induce
microchips. an oscillating electric field,
The team of researchers which changes the effective
led by Hong-Son Chu at the size of the tunneling gap
A*STAR Institute of High and therefore the number of
Performance Computing and electrons that can cross the gap
Christian Nijhuis at the National and interact with SPPs.
University of Singapore believe “By doing away with the need
that SPPs, electromagnetic for light sources and detectors,
surface waves that exist at the devices based on this mechanism
interface of two materials, would be intrinsically fast,”
could be used to seamlessly link This illustration shows two tunnel junctions coupled together by a plasmonic says Chu. “Our work has
photonic devices and electronics. waveguide in the center. When a voltage is applied to the source junction, tunneling attracted interest from research
electrons excite surface plasmons, which propagate along the plasmonic waveguide
“SPPs essentially contain communities and industries,
and modulate the tunneling current at the detector junction. Inset: A light emission
light confined to dimensions image of tunnel junctions, showing plasmons scattering from the end of the with potential applications in
smaller than its wavelength, plasmonic waveguide. three-dimensional integrated
© 2018 Du Wei, National University of Singapore

and they function like photonic circuits and high bandwidth
elements, carrying information plasmonic transducers that is quite slow. Chu and co- memory devices. For example,
at high speeds,” says Chu. operate at optical frequencies, workers realized it would be there is a need for small,
“However, the SPPs offer the best and we achieved an electron- much faster to produce SPPs high-speed interconnectors to
of both worlds because they have to-SPP conversion efficiency of by direct electrical means, improve processing speeds.”
the operational speed of optical more than 10 per cent.” so they designed transducers
elements as well as a small size Most existing plasmonic comprising aluminum and 1. Du, W., Wang, T., Chu, H.-S. & Nijhuis,
C. A. Highly efficient on-chip direct
suitable for nano-electronics devices require light sources gold electrodes, separated by a
electronic-plasmonic transducers.
applications. We have developed such as LEDs to generate two nanometer-thick layer of
Nature Photonics 11, 623–627 (2017).
the first on-chip electronic- SPPs. This indirect method aluminum oxide that acts as an

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can efficiently map the vessel an absorbing Markov chain,
network. which ‘locks in’ the traced path
“We have spent years up to the current node, and then
analyzing retinal blood vessels, applies a random walk algorithm
IMAGE where a challenge is always to to probe an image for the next
PROCESSING
single out each vessel from the blood vessel direction.
rest or to separate artery from In this way, their image
vein vessels,” says Cheng Li from processing algorithm can start
the A*STAR Bioinformatics from a labeled node, such as
Institute. “We have developed a major branch, and trace
an algorithm that can trace a the blood vessels to form a
network from a few marked or connected network in a way
EYES ON THE ‘labeled’ nodes, and it works similar to how a physician would
ROAD FOR RETINA especially well for large-scale
networks of, say, millions of nodes
tackle the problem.
In application to real
MAPPING even with very few known labels.” retinal images, the algorithm
In their theoretical study, Li outperformed other state-of-the-
An image processing algorithm and his team explored the use art approaches, and matched the
designed to follow directional of a well-established algorithm in accuracy of human tracing.
image processing, called “We developed this
features shows promise for mapping
the Markov chain, to better follow algorithm out of our very
the blood vessel networks in the eye the complex branching networks practical biomedical imaging
of blood vessels in the retina. experience in blood vessel
A Markov chain is a statistical tracing over a number of years,”
representation of a sequence, in says Li. “Our approach is simple,
More accurate and efficient indicator for many clinical this case of connected nodes, easy to implement, and has many
mapping of retinal blood vessels disorders including diabetes, where an element in the sequence important applications including
using a path-following image high blood pressure, arterial is independent of everything that image classification, and network
processing scheme, developed hardening, and occlusion of came before it. For a blood vessel, and link analysis.”
by an A*STAR-led research retinal arteries. However, tracing this means that its direction of
team, could help improve retinal retinal blood vessels is a time- branching from a given point 1. De, J. Zhang, X., Lin, F. & Cheng, Li.
Transduction on directed graphs
scanning and medical diagnosis1. consuming process requiring could be entirely random and via absorbing random walks. IEEE
The blood vessels found on training and skill, which not dependent on the path of the Transactions on Pattern Analysis and
the retina at the back of the eye would be better performed by a vessel that came before it. Li’s Machine Intelligence, advance online
are an important diagnostic reliable automated process that team took this further to adopt publication 11 Aug 2017.

A retinal image and
the blood vessel
network traced
by the ‘absorbing
random walk’ image
processing algorithm.
© 2017 IEEE. Reprinted, with permission, from Ref 1

44 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

ADVANCED
MATERIALS

PICKING
WINNERS FROM
MILLIONS OF
POSSIBILITIES
A clever simulation scheme
helps identify the most
promising compositions of
two-dimensional materials

A high-throughput scan arrangements of transition are huge. So we developed a alloy structures,” says Tan.
of possible compositions for a metals (like molybdenum or high-throughput computational The scan, conducted in
new class of materials known titanium), carbon and nitrogen. method to predict the probable collaboration with Drexel
as MXenes gives researchers These characteristics are reflected structures and stable phases of University in the US, revealed
invaluable direction for picking in the name ‘MXene’ — the ‘M’ different MXene alloys across that molybdenum-based MXenes
the best candidate from the represents metal atoms, the ‘X’ all compositional ranges and mixed with vanadium, tantalum,
millions of possible material denotes carbon and nitrogen, temperatures.” niobium or titanium, appear to
recipes1. The simulation study while the ‘ene’ suffix signals the Although there are form the most stable ordered
by researchers from the A*STAR materials’ 2D atomic structure. many possible MXene alloy structures. Titanium however
Institute of High Performance compositions, most will not be tends to form stable ‘asymmetric’
Computing is a significant “Our approach stable. The challenge faced by ordered structures that were
advancement in the field of enables quick material scientists has been how previously not considered viable.
MXenes, which have exciting evaluation of the to efficiently sweep through “Our scan allows us to predict
potential in next-generation the huge number of alloy the structures of MXene alloys
formation energies
energy storage applications. configurations to identify those that are yet to be fabricated
Two-dimensional (2D)
of millions of MXene with the lowest formation energy and estimate the likelihood
materials are a relatively new
alloy structures.” and hence highest stability. of their fabrication from a
class of materials that display a Conventional ‘first principles’ thermodynamics viewpoint. And
wide range of unusual properties “Since MXenes are new, calculation approaches are too for known MXene alloys, our
associated with their ability there’s still much to be learned computationally intensive for predicted structures are consistent
to constrain the movement about their structure and such a scan to be feasible. with experimental results.”
of electrons and energy in a properties,” says Teck Leong Tan “Our approach uses what’s
©onurdongel/E+/Getty

2D plane. The MXene alloys from A*STAR. “As MXene alloys called a cluster expansion method 1. Tan, T.L., Jin, H.M., Sullivan, M.B.,
Anasori, B., & Gogotsi, Y. High-
are a very recently discovered are formed by mixing different to ‘learn’ the effective interactions throughput survey of ordering
class of 2D materials, which types of transition elements between atoms, thus enabling configurations in MXene alloys across
could conceivably consist of at different compositions, the quick evaluation of the formation compositions and temperatures. ACS
any of millions of possible alloying possibilities in MXenes energies of millions of MXene Nano 11, 4407–4418 (2017).

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

Researchers at A*STAR “This finding has the
have identified the ‘brakes’ potential to change forever
that keep heart muscle cells the way heart failure patients
from dividing and healing are treated,” comments Foo.
CARDIAC damaged heart tissue1. This “Right now, drugs for patients
REPAIR
finding raises the possibility with cardiovascular disease
of developing treatments that only stem the progress of
target these brakes to stimulate the disease. Regenerative
heart repair. treatments that target
More people die of SingHeart could reverse the
cardiovascular disease than of course of the disease, which
HEALING any other cause. One reason would be a revolutionary way
DAMAGED the disease is so often fatal
is that heart muscle cells,
to treat heart failure.”
The researchers discovered
HEARTS or cardiomyocytes, are very SingHeart by analyzing
slow to divide and replenish gene expression in single
Scientists believe they have discovered themselves. Consequently, cardiomyocytes derived from
why heart muscle cells regenerate so damage to the heart is often healthy and diseased hearts
irreversible. Scientists have of both mice and humans.
slowly, opening potential for inducing
long searched for a way to Their analysis revealed that,
damaged hearts to repair themselves induce cardiomyocytes to in diseased hearts, certain
regenerate at higher rates. cardiomyocytes activate
Now, Roger Foo and genetic programs related to
his co-workers at the cell division — the first time
A*STAR Genome Institute that different subpopulations
of Singapore have identified of cardiomyocytes have been
the culprit responsible for shown to have different gene
the slow regeneration rates expression in response to
of cardiomyocytes — a long stress. Further analysis showed
noncoding ribonucleic acid that SingHeart plays a role in
(RNA) the team labeled blocking genes responsible for
‘SingHeart’. cell division in cardiomyocytes.
Noncoding RNA does The team is now exploring
not code for proteins and whether this finding can be
previously had no known used to develop new treatments
useful role, leading some for cardiovascular disease.
to call it ‘junk RNA’. But “We’re very hopeful this
there is now recognition will lead to future clinical
that noncoding RNA treatments,” says Foo. “If
plays an important not through SingHeart, then
role in modifying the through other molecules that my
© SEBASTIAN KAULITZKI/Science Photo Library/Getty

expression of genes that team are also hunting for.”
code for proteins. In the
case of SingHeart, Foo 1. See, K., Tan, W. L. W., Lim, E.
H., Tiang, Z., Lee, L. T. et al.
and co-workers found
Single cardiomyocyte nuclear
that the noncoding RNA
transcriptomes reveal a lincRNA-
regulates genes that regulated de-differentiation and
control the ability of cell cycle stress-response in vivo.
cardiomyocytes Nature Communications 8, 225
to multiply. (2017).

46 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

Coil stator Coarse Stage

ENGINEERING
Flexure

MAKING LIGHT
WORK OF Fine Stage
NANOPOSITIONING
An integrated design strategy
Interferometer
lowers the mass and costs of
motors that move objects nano- An integrated nanopositioning device can achieve high precision with a simpler and less expensive
meters at a time design than typically used.

Probing intricate cells or This type of configuration, can be controlled with the same applied force ‘ripples’ through
high-tech microchip components known as serially-actuated electromagnetic machinery the nanopositioner and impacts
requires ‘nanopositioners’ dual-stage design, has inherent used to drive the coarse motor small-scale movements.
that can scan large areas with problems according to Daniel — eliminating the weight and Fabrication of an
extremely small steps. Normally, Tat Joo Teo from the Singapore expense of troublesome cables. experimental prototype revealed
these positioners have separate Institute of Manufacturing the potential of the researchers’
fine- and coarse-movement Technology (SIMTech) at A*STAR. “The parallel- integrated positioner and
stages, but A*STAR researchers “In a traditional serially-actuated actuated dual- analytical model. As measured by
have introduced a parallel- design, power cables are linked to stage design gives a laser interferometer, the device
actuated system that integrates the fine-motion stage to energize could move in 20 nanometer
reasonably good
the two units for improved the actuators. These cables cause steps without being sensitive
performance even
energy efficiency1. substantial disturbance, and limit to millimeter-scale coarse
When engineers design the performance of the entire
with a low-cost movements — findings that may
bearings for guiding moving motion system.” coarse stage.” usher in a new era of inexpensive
parts, they typically work with Teo and his collaborators nanopositioning devices.
tolerances of a few micrometers. from SIMTech and the National The challenge with this “The parallel-actuated dual-
Nanopositioning devices, University of Singapore integrated design, notes Teo, lies stage design gives reasonably
however, need precision considered a different approach in finding the right combination good performance even with
© 2017 IEEE. Reprinted, with permission, from Ref 1.

standards up to a thousand times to constructing nanopositioners. of mechanical characteristics a low-cost coarse stage,” says
greater. To achieve this kind of Instead of conventional such as stiffness and damping. Teo. “We plan to commercialize
precision motion, piezoelectric piezoelectric actuators, they While conventional positioners the system to benefit our
crystals that slightly expand or chose a magnetic linear motor can analyze the properties manufacturing industry.”
contract with voltage stimulation as a means to establish fine of controllers, actuators, and
are usually combined with an motion. Then, they coupled this mechanical stages independently, 1. Zhu, H., Pang, C. K. & Teo, T. J. A
flexure-based parallel actuation
active feedback sensor. Then, the motor with hinge-like flexure the team had to find a way to
dual-stage system for large-stroke
fine-motion crystal is mounted bearings attached to the coarse optimize these three elements
nanopositioning. IEEE Transactions
on to the moving part of a translator. The flexure system concurrently. To do so, they on Industrial Electronics 64, 5553–
linear actuator capable of large offers nanometer-scale movement established an analytical model 5563 (2017).
displacements in a single stroke. without dry friction and critically, capable of predicting how

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

the troublesome intermediate. materials can be seen as a
This ‘one-pot’ Suzuki-Heck greener approach.” The team
reaction offers a more efficient now hopes to improve the
way to make stilbenes, method and use it to make
CHEMISTRY potentially saving costs and stilbene derivatives for organic
reducing waste associated with electronics.
purification of the intermediate
product. 1. Das, U. K., Clément, R., Johannes, C.
W., Robins, E. G., Jong, H. & Baker,
The catalyst partners R.T. One-pot Suzuki-Heck relay to
palladium with a bulky prepare industrially valuable inter-
phosphorus-containing molecule mediates using the Pd-Cy*Phine

AN ALL-IN-ONE called Cy*Phine. The team tested
the catalyst’s performance in the
catalyst system. Catalysis Science &
Technology 7, 4599 (2017)

CATALYST Suzuki coupling reaction using
48 different reaction conditions,
Palladium catalyst speeds varying the solvent and other
up two separate reactions, reagents. After identifying the
recipe that gave the best results,
making useful molecules
the researchers repeated this
in a single process optimization process for the one-
pot Suzuki-Heck reactions.
This gave them a
reliable method that was
A palladium catalyst benzene molecule. After the used to make a broad range
developed by A*STAR product of this reaction, styrene, of model compounds that
researchers offers a reliable is extracted and purified, a resembled commercial targets.
and efficient way to create a second step, called a Heck The reactions typically gave
molecular structure that is reaction, tacks another benzene average yields of 64–91 per cent
commonly found in medicines ring on the other end of the for each step, comparable to
and electronic materials1. carbon-carbon double bond. The performing the reactions
The structure is known product of the first step, or ‘the separately. “However, being
as a stilbene fragment, which intermediate’, however, is often able to perform one-pot
comprises two benzene rings, unstable, making it difficult to reaction sequences provides
connected by two carbon atoms handle and lowering the overall a quicker and more
with a double bond between yield of the process. economical strategy,”
them. The benzene rings are able says Jong. “The savings
to carry a host of other chemical “The savings of of time, solvent, reagents,
groups, so stilbenes make up time, solvent, waste, and
a large and diverse family of reagents, waste purification
molecules, which can be used in
and purification
potential treatments for central
materials can be
nervous system disorders and
as the active material in certain
seen as a greener
organic light-emitting diodes approach.”
(OLEDs) used in advanced
© MOLEKUUL/SCIENCE PHOTO LIBRARY

displays and lighting. Howard Jong of the
Until now, stilbenes A*STAR Institute of Chemical
have typically been made & Engineering Sciences and
in a two-step process, with collaborators at the University Pterostilbene (pictured), a
defensive chemical found in
each step relying on different of Ottawa, Canada, have now blueberries, is an example of
palladium catalysts and reaction shown that a single palladium a functional molecule that
conditions. The first step, known catalyst can carry out both of contains the stilbene motif.
as a Suzuki coupling reaction, these steps in one reaction vessel,
adds a two-carbon unit to a which avoids the need to isolate

48 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

FLAT-PACKED
OPTICAL COMPONENTS
OPTICS
Nanostructured thin-films that can bend light by large angles
could be a replacement for bulky glass optical components

Surfaces that efficiently redirect
the propagation of light have
been developed by A*STAR
researchers. Ramón Paniagua-
Domínguez, working with
colleagues from the A*STAR
Data Storage Institute and
Nanyang Technological
University, has invented
compact and light-weight
optical components that could
be integrated into portable
optoelectronic devices.
Traditional glass optical
components alter the
propagation of light through
reflection and refraction. They
tend to be three-dimensional:
a lens, for example, requires
a curved surface that focuses A metasurface with fish-like elements redirects an incoming beam of light into a new direction.
light to a point. But these bulky
elements add weight, to mobile bending light at very large The researchers this structure demonstrated
phone cameras for example. angles difficult. demonstrated this concept broadband operation, effectively
A flatter alternative is found Paniagua-Domínguez experimentally by etching their bending light across wavelengths
in metasurfaces, which consist and the team have achieved nanoantenna array design into in the green and blue parts of the
of an array of structures, each efficient optical channeling a thin film of titanium dioxide spectrum.
smaller than the wavelength at any desired angle using a on a glass substrate. One design “Based on this concept,
of light, engineered to modify metasurface comprising an array they investigated had a structure we are now working towards
the characteristics of incident of asymmetric nanoantennas. Just that loosely resembled a fish, a flat lens with an extremely
light. As an optical beam hits like normal antennas, they alter with a ring surrounding the tip large numerical aperture,” says
this surface, it scatters off the scattering directivity patterns of a triangle. The dimensions Paniagua-Domínguez. “That is,
the subwavelength elements, by suppressing or enhancing of the fish were all below 300 a lens that can focus light into a
forming an output beam with emission at different angles. nanometers, much smaller very small spot or resolve very
© 2018 A*STAR Data Storage Institute

chosen properties. This can, “Our new approach goes beyond that the wavelength of the small objects or features.”
for example, be used to bend the standard design, which is to incident light. With this novel
the incoming beam into a use phase mapping,” explains approach they were able to bend 1. Khaidarov, E., Hao, H., Paniagua-
Domínguez, R., Yu, Y. F., Fu, Y. H.,
new direction. However, the Paniagua-Domínguez. “We more than 50 per cent of the Valuckas, V., Yap, S. L. K., Toh, Y. T., Ng,
efficiency with which the light foresee that these metasurfaces energy of an incoming beam J. S. K. & Kuznetsov, A. I. Asymmetric
is redistributed into the correct may out-perform traditional of green light at an angle of up nanoantennas for ultrahigh angle
direction decreases sharply bulk optics not only in terms of to 73 degrees. Moreover, and broadband visible light bending.
Nano Letters 17, 6267–6272 (2017).
for increasing angles, making efficiency, but also functionality.” contrary to previous approaches,

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

that the bridges grew outwards
from the center of the cell during
The structure of a cell, division and then back into
microtubule indicated in the cells afterward. A network
cell in dark blue.
of microtubules grew out of
each bridge, and the bridge and
network proved to be crucial
for the transport of adhesive
proteins to the cell membrane.

“This was a chance
discovery. It’s not
something we or
others could have
hypothesized
based on previous
work.”

The team is also investigating
why the bridges persist rather
than breaking down as they do
in other cells. “We think that the
mechanisms that normally cut
the bridges — the proteins and
molecular machinery — are all
there in the early embryo, but

PUTTING THE just aren’t active. Something
represses them in the early
CELL ‘BONES’ IN ORDER embryo,” explains Plachta.
BIOLOGY In addition to organizing
Tubular bridges organize the skeletons of microtubule growth and
cells in the early embryo providing a scaffold for
transport, these bridges may also
mechanically connect embryonic
cells to coordinate the dynamics
of their growth and division
during development. “We don’t
Scientists at A*STAR have known as the centrosome serves were retained, so that got us know much about that at the
discovered how cells in the as a microtubule-organizing interested,” says Plachta. “Is moment, but we’re studying how
nascent embryo organize center (MTOC) in most animal there something special about it might work,” says Plachta.
the ‘bones’ that make up the cells, including older embryos. these bridges and these cells in “Each cell is connected to its
skeleton of the cell, known Plachta’s team was examining the early embryo?” sister through this shared
as microtubules. While this the microtubules during To find out, Plachta’s team skeleton. When a cell changes
discovery has resolved one the first few cell divisions in disrupted the bridges with a laser shape or gets squeezed, how does
mystery, it also raises a range of mouse embryos, which lack pulse. This led to the breakdown the microtubule skeleton change
© lvcandy/DigitalVision Vectors/Getty

new questions. centrosomes, when they noticed of microtubules in the cells and a in that cell and in the sister cell
“This was a chance discovery. that neighboring cells were change in cell shape. Destroying connected to it?”
It’s not something we or others connected by microtubule the MTOC in other cells has
could have hypothesized based bridges. Microtubule bridges similar consequences, suggesting 1. Zenker, J. White, M. D., Templin, R. M.,
Parton, R. G., Thorn-Seshold, O. et
on previous work,” says Nicolas usually form between dividing to the team that the bridges may al. A microtubule-organizing center
Plachta of A*STAR’s Institute cells during mitosis, but substitute for the MTOC in the directing intracellular transport in
of Molecular and Cell Biology, they are normally broken early embryo. the early mouse embryo. Science
who led the study. A structure down afterwards. “But these Further observation revealed 357, 925–928 (2017).

50 A*STAR RESEARCH  Issue 10 | January – March 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

HIGH-
RESOLUTION
PRINTING

N4 te
Si 3 s tra
b
Su
Si
FLOATING
NANOSTRUCTURES 20 µm
FOR BETTER COLOR
(above) A schematic of the surface
the team created featuring tiny silicon
nanostructures.
Extremely high-resolution color images are
(left) The team’s reproduction of
produced using silicon nanostructures that Kandinsky’s Murnau Street with Women.

imitate particles floating in free space

The detail in color images is five years, and now we have 70-nanometer silicon nitride nanodisks, as well as nanorings,
limited by the size of pixel that solved the problem of limited layer. The nitride acts as an ‘anti- on their substrate, until they
can be printed. Recent advances color saturation,” says Yang. reflective’ coating, effectively were able to achieve high-
in nanotechnology have opened Unlike previous efforts with tricking the incident light into resolution images with over
the possibility of printing at nanostructures made from behaving as if it is not there and 120 per cent of the sRGB color
incredible resolutions of around precious metals such as silver the nanodisks are floating in free palette — the best quality
100,000 dots per inch, by using and gold, the team used space. color from any nanostructure
metallic nanostructures that silicon, which is cheap, readily “An important requirement system of this resolution. They
resonate in response to incident compatible with existing for ideal color reflection is to demonstrated the system by
light. However, the colors that electronics, and has useful meet Kerker conditions, where accurately reproducing a print
these systems produce are optical properties. incident light excites magnetic of Wassily Kandinsky’s
limited, and cannot fill the and electric dipoles in a silicon famous painting Murnau
standard Red Green Blue (sRGB) “We have been particle in such a way that the Street with Women.
palette used in most devices and working on ultra- particle scatters light entirely Yang and Dong are hopeful
the Internet. high resolution in one direction,” explains that their new design for
© 2018 A*STAR Institute of Materials Research and Engineering

Now, a team including Joel color printing for Yang. “In free space, the nanostructure printing could
Yang, Arseniy Kuznetsov and uniform surroundings of eventually be accessible to
the past five years,
Zhaogang Dong at the A*STAR the particle allow Kerker everyone via a desktop device,
and now we have
Institute of Materials Research conditions to be met. A and could also have applications
and Engineering (IMRE), and
solved the problem substrate will generally in miniaturized displays, data
Data Storage Institute (DSI) have of limited color break spatial symmetry, but storage and security prints for
produced a new printing system saturation.” if the substrate does not reflect, identifying counterfeits.
with nanostructures made from the situation is equivalent to
silicon, achieving a spread of The researchers used light propagating through 1. Dong, Z., Ho, J., Yu, Y. F., Fu, Y. H.,
Paniagua-Dominguez, R. et al.
colors even wider than sRGB1. electron-beam lithography free space.” Printing beyond sRGB color gamut
“We have been working and reactive-ion etching to Yang, Dong and co-workers by mimicking silicon nanostructures
on ultra-high resolution produce tiny silicon disks, experimented with several in free-space. Nano Letters 17,
color printing for the past 130 nanometers high, on a different sizes and spacings of 7620–7628 (2017).

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

CANCER CELL DRUG SPIN

© Image Source/Getty; © 2018 A*STAR Institute of Medical Biology; Reprinted from X. Fan et al., Polymer Chemistry 8, 5611 (2017) with permission of The Royal Society of Chemistry; © RICHARD KAIL/Science Photo Library/Getty
RESEARCH BIOLOGY DELIVERY MEMORY

A BLOOD TEST FOR PUTTING MUSCLE REACH FOR DYNAMIC SOLUTION
CANCER RECURRENCE NUCLEI IN THEIR PLACE THE STARS FOR ACCURATE READING
Assay for genetic quirk Microtubules anchored Star-shaped nanoparticles A sensing scheme that responds
can provide a wealth of to proteins in the nuclear that release their drug payload dynamically to voltage
information on patient membrane position only after entering cells could fluctuations could improve data
disease status and prognosis. muscle cell nuclei. improve current treatments. reading accuracy.

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52 A*STAR RESEARCH  Issue 10 | January – March 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

If you are passionate about future-ready science and research,
focus your sight now on an A*STAR scholarship. SECURITY SCREENING

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