CELEBRATING - Institute of Molecular and Cell Biology

Transcription

of Molecular
and Cell Biology
IMCB Institute
Institute of Molecular and Cell Biology
IMCB
INSTITUTE OF MOLECULAR
AND CELL BIOLOGY
Institute of Molecular
and Cell Biology
IMCB
C
IInstitute
i
off M
Molecular
l
l and
d Cell Biology
and Cell Biology
INSTITUTE OF MOLECULAR AND CELL BIOLOGY
IMCB
CELEBRATING
IMCB
of Molecular
Institute of Molecular and Cell Biology IMCB Institute
and Cell Biology
30
AND CELL BIOLOGY
IMCB
Institute of Molecular and Cell Biology and Cell Biology
of Molecular and Cell Biology
OF
Institute of Institute
IInstitute
tit t offYEARS
Institute of Molecular and
Cell Biology
g
Mo
olecular
Molecular and aand Cell
Institute
i
of IMCB
Cell Biology BiologyEXCELLENCE
Molecular and
IMCB
C
IN SCIENCE
AND CELL BIOLOGY
Institute of Molecular and Cell Biology Institute of Molecular and Cell Biology
IMCB Institute of Molecular and Cell Biology Cell Biology
Institute off M
Molecular
l
l and
d Cell
C Biology
of Molecular
Institute of Molecular and Cell Biology IMCB Institute
and Cell Biology
and Cell Biology
IMCB INSTITUTE OF MOLECULAR
IMCB
IMCB
AND CELL BIOLOGY
Institute of Molecular and Cell Biology Institute of Molecular
INSTITUTE OF MOLECULAR AND CELL BIOLOGY and
61 Biopolis Drive, Proteos, Singapore 138673
Fax: +65 6779 1117
Email: [email protected]
http://www.imcb.a-star.edu.sg/php/main.php
Cell Biology
Celebrating 30 Years of
Excellence in Science
Copyright © 2015
Agency for Science, Technology and Research
All rights reserved.
No part of this publication may be reproduced, stored in a retrieval system
or transmitted in any form or by any means, electronic, mechanical,
photocopying, recording or otherwise, without the prior written permission
of the copyright holder.
61 Biopolis Drive, Proteos
Singapore 138673
2
CELEBRATING 30 YEARS OF EXCELLENCE IN SCIENCE
Contents
Message from A*STAR Chairman
Message from BMRC Executive Director
Preface by IMCB Executive Director
pg 5
pg 6
pg 7
A Tradition of Scientific Excellence
pg 9
Timeline
pg 10
Beginnings
pg 12
Building momentum
pg 16
A sign of things to come
pg 22
From the fish tank to the open seas
pg 24
Personal Perspectives
pg 28
Sydney Brenner
pg 30
Wanjin Hong
pg 31
Chris Tan
pg 32
Louis Lim
pg 33
Philip Yeo
pg 34
Pin Lim
pg 35
Richard Sykes
pg 36
World-Class Research
pg 37
Infectious Diseases: Know the enemy
pg 38
Cancer: The enemy within
pg 40
Development: How did we get here?
pg 42
Genomics: Where do we come from?
pg 44
Structural Biology: Form begets function
pg 46
Cell & Molecular Biology: Understanding the building blocks of life
pg 48
Cell signaling: Sending the right message?
pg 50
New technologies: Bringing it first to Singapore
pg 52
Continuing scientific excellence: Hot off the press
pg 56
A Look to the Future
pg 61
Our up and coming PIs
pg 62
Training the next generation
pg 66
Alumni contributions
pg 72
Partnering industry
pg 77
Joint PIs
Acknowledgements
pg 82
pg 88
T
he success of the IMCB experiment would not
have been possible without the contributions
of thousands of IMCBians and friends of the
institute. This booklet only mentions a few
achievements, but we acknowledge all past
and present IMCBians, partners and friends.
3
4
5
Message from
A*STAR Chairman
and industry to deliver impactful translational research.
In 2014, IMCB developed four monoclonal antibodies
that were out-licensed for commercialisation. This
year, IMCB spin-off, MerLion Pharmaceuticals, also
achieved FDA approval to use its anti-bacterial drug for
treating ear infections. This is the first novel drug from
a Singapore company to achieve FDA approval.
Chuan Poh Lim
Chairman
Agency for Science,
Technology and Research
T
he founding of IMCB marks Singapore’s
pioneering effort into the field of biomedical
sciences. Established in 1985 to develop
research capabilities and scientific talent in
biomedical sciences, IMCB has played a foundational
role in developing biomedical sciences research in
Singapore and catalysing the growth of biomedical
sciences industry as the fourth pillar of the country’s
economy.
Vanda Chris Tan Yin Hwee
IMCB also placed Singapore on the map of biomedical
sciences research in the world. The institute built up
its research capabilities rapidly and gained international
standing within a decade. IMCB published its work in
many high-impact scientific journals and developed
collaborations with international pharmaceutical
and biotech companies. These very quickly placed
Singapore at the forefront of Asia’s life science and
won IMCB international acclaim, most notably the 5th
Nikkei Prize in 2000, which recognised the institute as
the first major centre of biomedical research in Asia.
IMCB’s strength in foundational research has been
instrumental in paving the way for downstream
development of therapeutics and diagnostics. One
example is IMCB’s capabilities in antibody studies,
which enabled Genelabs Diagnostics’ to rapidly develop
the SARS detection kit at the height of the crisis in
2003. The institute also works closely with clinicians
As the first biomedical sciences research institute in
Singapore, IMCB became the natural cradle to spawn
the next generation of scientific talent in the field of
biomedical sciences. This was indeed the intent behind
the establishment of IMCB, to train the talent required
to catalyse the growth of the biomedical sciences
industry. To date, IMCB has trained more than 260
PhDs and also attracted many talented scientists from
across the globe to work in Singapore. Some of them
are still with IMCB or within A*STAR, and others are
in the universities or industries including a few who
are running their own biotech companies such as Dr
Rosemary Tan (CEO, Veredus Laboratories) and Dr
Thuan D Bui (CEO, i-DNA Biotechnology)
IMCB’s 30th anniversary is a meaningful occasion for
us not only to celebrate how far IMCB has come but
to look forward to the next 30 years where IMCB will
continue to sustain its research excellence and talent
generation while sharpening its industry relevance
and impact. With its rich heritage, I am confident that
IMCB’s strengths in both discovery and translational
research will continue to advance science and develop
innovative technology that will bring about significant
societal benefits.
Chuan Poh Lim
Chairman
6
Message from BMRC
Executive Director
Benjamin Seet
Executive Director
Biomedical
Research Council
Agency for Science,
I
t is not often that an institute of science becomes
the national flagship to transform an economy, but
this would clearly be the case for IMCB.
The story goes that Sydney Brenner, when he was
invited to Singapore in 1983 to advise the government
on what it took to create a biotechnology industry,
recommended that it had to start with establishing
a modern biomedical research institute. Then Prime
Minister, Lee Kuan Yew, was said to have replied that
we were still primarily a nation of technicians and not
scientists. Brenner was quick to respond that Singapore
would remain a nation of technicians if we didn’t do
something about it, and so began Singapore’s journey
in the biomedical sciences and the establishing of IMCB
in 1985, followed by the creation of Biopolis in 2003.
In the past decade alone, biomedical manufacturing
grew almost five-fold to a peak of $29 billion in 2012
to contribute towards 5% of the national GDP. The
number of jobs trebled to exceed 24,000 in both
manufacturing and R&D. In many ways, this story
of growth is deeply intertwined with that of IMCB’s
development.
I can still recall how as a medical student at NUS, I had
been impressed with the glass building that housed
IMCB on top of the hill. And of how I marveled at the
futuristic, interconnected buildings of the Biopolis when
I first ventured into its compounds some 15 years later.
Today, it is no longer just the buildings that impress
me. Instead, it is about how one institute catalysed
an entire biomedical science economy and how it
brought Singapore from the scientific backwaters to an
internationally recognised hub for science and research.
More importantly, it is about people, and how IMCB’s
alumnus has now taken on leadership roles in our
research institutes and universities, and play important
roles in industry.
On this note, it leaves me to congratulate IMCB for
three decades of outstanding research, and to express
my thanks for its having helped make a difference for
Singapore.
Benjamin Seet
Executive Director
Biomedical Research Council
7
Preface by IMCB
Executive Director
Wanjin Hong
Executive Director
and Professor
and Cell Biology
Agency for Science,
2
015 marks the 30th anniversary of IMCB, which
was born out of a commitment by the Singapore
government to establish a biomedical research
hub here. This commemorative publication
traces the history of IMCB, a pioneering institution in
a three-decade-long initiative to transform Singapore
from a manufacturing economy into a knowledgebased economy.
A Tradition of Scientific Excellence charts the first 15
years under the helm of IMCB founding director Chris
Tan. It recounts IMCB’s early days at the National
University of Singapore before its move to Biopolis in
2004, and takes the reader through pivotal moments
in IMCB’s history, such as when it won the 5th Nikkei
Asia Prize and the 2003 National Day Award.
In the chapter on Personal Perspectives, we hear from
the pioneers, scientists and advisors who have made
IMCB possible through their vision and perseverance.
Sydney Brenner, Chris Tan, Louis Lim, Nam Hai Chua,
Philip Yeo, Pin Lim and Richard Sykes contributed
immensely to launching IMCB in the early 1980s. Today,
IMCB is a globally recognised hub in basic discovery
research, translation and innovation, and we thank
these pioneers for their contributions.
World-Class Research covers the high impact research
taking place at IMCB. The section is divided into
eight parts: Infectious disease, cancer, development,
genomics, structural biology, cell & molecular biology,
cell signalling, and new technologies. Scientific
discoveries at IMCB range from the identification of
PAK kinases, components of asymmetric cell division
and crucial mammalian SNARE proteins in the 1990s to
the completion of the fugu genome in 2002.
In the final chapter A Look to the Future, we discuss
IMCB’s view to future challenges. IMCB is undergoing
a fundamental shift from basic research to tackle
problems of relevance to human diseases, such as
cancer. We remain focused on talent renewal through
our IMCB Junior Investigator and Independent Fellow
programmes, in addition to fostering close partnerships
with industry partners. In 2014 alone, we had 14 close
industry collaborations spanning pharm-bio, med-tech,
personal care and the food and nutrition sectors.
I hope that by flipping through these pages, you will
join us on an enjoyable journey through three decades
of stories and achievements at IMCB. Please enjoy
reading this book and do continue to support us and
our mission.
Wanjin Hong
Executive Director and Professor
8
9
The Institute of Molecular and Cell Biology (IMCB) is a member of Singapore’s Agency for Science, Technology and
Research (A*STAR) and is funded through A*STAR’s Biomedical Research Council (BMRC).
Independent
research groups:
45
Staff
members:
>400
staff members
Established in:
1985
Major fields of research:
Cell
Biology
Developmental
Biology
PhD students trained at IMCB:
PhD
students
>260
Structural
Biology
Genomics
Infectious
Diseases
Cancer
Biology
Number of papers published:
>2,000
research papers in
top international
peer-reviewed
journals
Translational
Research
Yearly
citation
since
2012:
>8,000
citations
Abbreviations
AI:
A*STAR Investigatorship Award
A*IF:
A*STAR International Fellowship
A*STAR: Agency for Science, Technology and Research
BII:
Bioinformatics Institute
BMRC: Biomedical Research Council
BMS:
Biomedical Sciences
BTI:
Bioprocessing Technology Institute
CNPR:
Centre for Natural Products Research
CSI:
Cancer Science Institute of Singapore
EDB:
Economic Development Board
ETC:
Experimental Therapeutics Centre
FDA:
Food and Drug Administration
GIS:
Genome Institute of Singapore
IMB:
Institute of Medical Biology
IMCB:
INL:
Institute of Neurology London
MOF:
MTI:
NCCS:
NMRC:
NBP:
NRF:
NSTB:
NTU:
NUS:
R&D:
RIEC:
RISC:
SBIC:
SIgN:
S&T:
Ministry of Finance
Ministry of Trade and Industry
National Cancer Centre Singapore
National Medical Research Council
National Biotechnology Programme
National Research Foundation
National Science and Technology Board
Nanyang Technological University
National University of Singapore
Research and Development
Research, Innovation and Enterprise Council
Research Incentives Scheme for Companies
Singapore Bioimaging Consortium
Singapore Immunology Network
Science and Technology
A Tradition
of Scientific
Excellence
1.
Beginnings
2. Building Momentum
3. A Sign of Things to Come
4. From the Fish Tank to the Open Seas
Astrocyte generated from a neural progenitor cell and stained with an antibody
against glial fibrillary acidic protein (GFAP) Image: Shuhui Lim and Philipp Kaldis
10
2002:
Timeline
CNPR was spun
off as MerLion
Pharmaceuticals.
1988:
1985:
Singapore’s first
life sciences
institute, IMCB,
was founded.
Its founding
director was
Chris Tan.
IMCB held the
first Gordon
Research
Conference
in Singapore.
1993:
1991:
The National
Science and
Technology
Board (NSTB)
was established.
IMCB undertook
a $60-million
joint venture
with Glaxo and
EDB to discover
bioactive
compounds via
the Center for
Natural Products
Research
(CNPR).
1989:
IMCB moved
into its own
building
at NUS
IMCB entered
into a 15-year
partnership
with Glaxo, for
research on
degenerative
brain diseases.
The team,
led by Louis
Lim, included
Thomas Leung
and Edward
Manser.
2001:
IMCB
founding
director Chris
Tan stepped
down, and
Wanjin Hong
took over
as Acting
Director.
An
international
consortium,
led by IMCB
and the Joint
Genome
Institute
of the US
Department
of Energy,
published the
draft sequence
of the fugu
genome in
Science.
2006:
The National
Research
Foundation
(NRF) was
established.
2004:
IMCB moved to
Biopolis. David
Lane took over as
Executive Director
of IMCB.
IMCB
licensed DNA
methylation
detection
technology to
Hitachi Asia
Ltd. for use in
clinical cancer
diagnostics.
1995:
The Institute
of Molecular
Agrobiology
(IMA) was
founded.
Thirteen of
the biomedical
research groups
at IMA were
later merged
with IMCB in
2002.
GeneSing,
IMCB’s first
spin-off
company, was
incorporated.
The company
develops human
healthcare
products for the
Asian market.
IMCB was
conferred the
5th Nikkei Asia
Prize in the
category of
Technology
Innovation for
its contributions
as the first
major centre
of biological
research in Asia.
IMCB and
Genome
Institute of
Singapore (GIS)
researchers
developed an
assay to detect
H1N1 swine flu
strains during
the 2009
pandemic.
IMCB hosted
the Euro Gold
Symposium
2011:
Wanjin Hong
appointed
Executive
Director of
IMCB.
The IMCB
Junior
Investigator
(IJI) Programme
was launched
to nurture
returning
A*STAR
scholars as well
as exceptional
young
scientists.
2010:
2000:
1992:
A research team
at IMCB, led
by Chris Tan,
completed and
published the
first sequence
of dengue virus
type 1.
2009:
The NSTB was
renamed the
A*STAR.
1999:
The National
Biotechnology
Programme was
established by
the Singapore
Economic
Development
Board (EDB) to
spearhead the
development of
biotechnology.
1987:
11
Stephen Cohen
became the
Acting Director
of IMCB.
2007:
2003:
IMCB codeveloped
two rapid
and accurate
diagnostic kits
during the
SARS outbreak,
which was
recognised by
a National Day
Award later
that year.
2005:
A PCR-based
malaria
diagnostic
kit, jointly
developed at
IMCB and NUS,
was launched
by Veredus
Laboratories
Pte Ltd.
Neal Copeland
took over the
helm of IMCB
as Executive
Director.
2014:
IMCB
developed
14 close
industry links
including
partnerships
with Procter
& Gamble
on skin
biology and
Johnson &
Johnson on
humanised
mouse
models.
2015:
IMCB launched
a collaboration
with Abcam to
develop a range of
rabbit monoclonal
antibodies for
diagnostic use.
MerLion
Pharmaceutical’s
lead antibacterial
candidate,
finafloxacin, was
approved by the
US Food and Drug
Administration
(FDA) for clinical
use.
IMCB celebrated its
30th anniversary
12
13
Beginnings
I
MCB began at a crossroads in Singapore’s history, as
an experiment by the EDB to see whether Singapore
could conduct credible biomedical research in spite
of its limited resources. Tasked to execute this
experiment were Goh Keng Swee, the architect of
Singapore’s economy; Nobel Laureate Sydney Brenner;
and Chris Tan, IMCB’s founding Director.
Growth, recession and research
In the years following Singapore’s independence in
1965, manufacturing played an important role in
providing jobs and growing the economy. As early
as the 1970s, the young nation saw two major
pharmaceutical companies open manufacturing plants
on its shores—Beechams in 1972, and Glaxo in 1979.
Encouraged by the success of the Quality Road plant
which produced one of the most widely prescribed
antibiotics, amoxicillin, Beechams opened a second
plant in 1982 to manufacture ranitidine hydrochloride,
the active ingredient of the gastric ulcer drug, Zantac.
By late 1982, sales of the new drug had propelled the
company into the top five pharmaceutical companies
in the world by sales, up from 25th position just a few
years before.
Early success notwithstanding, the recession of 1985
demonstrated that focusing on manufacturing alone
was not enough; a drastic change in direction was
required. Goh Keng Swee, who was then Deputy Prime
Minister, recognised that the future lay in research and
development, and quickly set about the search for the
right people to develop Singapore’s research sector.
1983
A timely visit
On the recommendation of his friend, British financier
Evelyn Rothschild, Goh Keng Swee came to know
about Sydney Brenner, who was Director of the UK
Medical Research Council’s Laboratory of Molecular
Biology, Cambridge at the time. Brenner was promptly
invited to visit Singapore, arriving in 1983 to give a
lecture on biotechnology under aegis of the Lee Kuan
Yew Distinguished Visitors Programme.
During his visit, he met then Prime Minister Lee Kuan
Yew and proposed the setting up of the IMCB to be
hosted by the NUS as a start to developing research
capability and manpower in the field of biotechnology.
When questioned as to the value of such an expensive
investment for Singapore, Sydney Brenner candidly
remarked to Lee Kuan Yew, “Prime Minister, if you
choose to continue on this path, you will remain a
nation of technicians.”
Approval letter for the establishment of IMCB
“
I was genuinely interested in helping a young country motivated to go in the
right direction…. This was to be an experiment in developing state-of-the-art biomedical
research at a national level in what was a third world country not too many years before.
I viewed it as an exciting venture and an exciting opportunity.
”
Nobel Laureate Sydney Brenner in Sydney Brenner: A Biography by Errol Friedberg
Sydney Brenner
14
1985
15
IMCB is widely considered a “proof of principle” that
Singapore could establish from scratch a biomedical
research community that operated to international
standards. Outside of Japan, and to some extent
China, there was little molecular biology in Asia to
speak of in the 1980s. From EDB’s perspective, IMCB
would serve to train talented scientists and act as a
magnet for attracting multi-national biotechnology
and pharmaceutical companies to set up R&D units in
Singapore.
Recruitment of the first Director
IMCB was officially launched by the then Vice Chancellor
of NUS, Prof Pin Lim, on January 23, 1985. After
that plans for the new institute were quickly set into
motion, with Sydney Brenner appointed as Chairman
of the Advisory Board. With the backing of Brenner, a
recognized trailblazer in biotechnology, IMCB began to
attract many top talents from across the globe.
However, there were also considerable hurdles. Recalling
those early days Chris Tan has commented “It was a
major challenge — the country was very mercantile at
the time, and it took a lot of soul searching for the
government to put funding into basic research.”
Planning for IMCB had reached such a stage that the
$25 million contract for building IMCB was given
out before the release of the Report of the Economic
Committee which recommended a focus on new
opportunities for economic growth such as in the
biotechnology sector.
Source The Straits Times © Singapore Press Holdings Limited.
Permission required for reproduction
One of the first appointments was Chris Y.H. Tan, a
Professor of medical biology and medical biochemistry
at the University of Calgary in Canada. A man on a
mission, Chris Tan recognised that his top priority and
challenge would be to attract the best talent to a little
known island state. He was, in his own words, willing
to “beg, borrow or steal” the best researchers from
North America and Europe.
“
On Christmas Eve of 1983
the then Deputy Prime Minister of
Singapore, Goh Keng Swee, called me
in Canada to ask if I would establish a
research institute, eventually christened
the Institute of Molecular and Cell
Biology (IMCB).
–Chris Tan
”
(L to R) Nam Hai Chua, Louis Lim, Charity Wei, Alan Porter and Chris Tan
at a site visit in 1986.
Chris Tan worked closely with his external academic
partners Sydney Brenner, Louis Lim, Nam Hai Chua, Alice
Huang as well as Pin Lim, the then Vice Chancellor of
NUS, in planning and construction of the new building
next to the National University Hospital (NUH). Ground
was broken in 1986 and only a year later IMCB started
up its research programmes on the site.
“
IMCB has become a beacon for young Asian
scientists thinking about returning to their home
countries. It has become a standard by which all
Asian institutes in science will be measured.
”
–Alice Huang, in 2000, then Dean of Science, New York University
16
17
Building
Momentum
I
MCB was officially launched by Pin Lim, on
January 23, 1985. The IMCB building was officially
inaugurated on October 2, 1987 on the NUS
campus by President Tony Tan, then Minister of
Education. Known fondly as the “blue fish tank on
the hill”, IMCB researchers and students certainly felt
under the spotlight. IMCB was up and running with
the first batch of 24 graduate students and 12 postdoctoral researchers in October 1987.
IMCB Building at Medical Drive, 1987
1989
A milestone for industrial partnership
Chris Tan, Alice Huang, Pearl Chua and Nam Hai Chua at the IMCB Building Opening ceremony
Meanwhile, Singapore had begun exploring the
possibility of developing a viable biotechnology
industry to diversify the economy. In 1988, Philip
Yeo, then Chairman of EDB, set up the National
Biotechnology Program (NBP) within EDB, and a
National Biotechnology Committee to spearhead the
venture into biotechnology. The NBP was headed by
Yong Sea Teoh who was also General Manager of
Singapore BioInnovations Pte Ltd, Singapore’s first
biotechnology investment fund.
By a fortunate twist of fate, Louis Lim, an IMCB
Advisory Board member from the Institute of Neurology
in London (INL) had connected with the director of
EDB’s office in London. With encouragement from
Philip Yeo and Richard Sykes, a research proposal
was submitted to Glaxo by Lim focused on the new
field of molecular biology. The proposal was deemed
highly complementary to Glaxo’s long term interests in
treatments for neurodegenerative conditions such as
Alzheimer’s disease.
Board members of SBI Sydney Brenner, Chris Tan, Philip Yeo,
Yong Sea Teo, Chin Nam Tan
Thus Glaxo responded positively in 1989 with a $50
million grant to be overseen by Louis Lim which funded
the GSK-IMCB group and its collaborative researchers
in INL (part of University College London). The research
programme on the underlying mechanism at play in
degenerative brain diseases gave Glaxo first right of
refusal over commercialisation or intellectual property
derived from projects. This program was highly
successful over its lifetime in identifying key brain
proteins (and drug targets) needed to establish and
maintain pathways needed for human memory. Its
legacy is the current small G-protein and kinase (sGSK)
group, headed by Ed Manser, which continues this
important work.
“
Twelve of us, representing several groups,
moved into the new building on Kent Ridge in March 1987.
Looking back, there were relatively few ‘teething troubles’,
though I do remember a mini flood when the air conditioning
failed, and having to call in the pest control to deal with a
plague of rats, bizarrely in the roof space.
”
–Alan Porter, Principal Investigator at IMCB from 1986 to 2008
18
19
1992
A new model of collaboration
The partnership between IMCB, EDB and Glaxo was
so successful that the trio went on to set up the CNPR.
This unit brought in state-of-the-art technology and
Glaxo know how to screen lead medicinal compounds
derived from natural products, including microorganisms, plants and marine invertebrates.
Antony Buss, who was head of CNPR from 2000,
became the first CEO of MerLion Pharmaceutical Pte
Ltd in 2002. The Singapore-based company has the
world’s largest and most diverse collection of natural
products (600,000). In 2015, the company received
US FDA approval for its lead antibacterial candidate,
finafloxacin.
“
When Richard Sykes, then
President of Glaxo Research, led a team
to Singapore in 1992 to discuss a project
on high throughput screening for active
molecules in natural products, we were
able to conclude an agreement on the
project parameters in one meeting
because of the tremendous goodwill that
existed among the parties,
–Yong Sea Teoh
”
Singapore’s efforts at cultivating a positive environment
for research were seen as so successful that there was
concern of a brain drain of scientific talent from West
to the East (TIME magazine, Nov 1994).
As the institute crossed its first decade, the attention
began to snowball, with coverage not only from
academic journals such as Nature and Current Biology,
but also industry analysts such as the Economist
Intelligence Unit.
IMCB research makes the front cover…
Nature on IMCB…
“…The molecular biology laboratory nearest to the
equator has done excellently ... It is a great triumph
to have won such a reputation in just under 8 years.”
(Vol. 374, p403, 1995)
“…has already established its name in the world of
science.” (Vol. 383, p14, 1996)
“...already approaching world-class standards in
research.” (Vol. 389, p117, 1997)
“...built an impressive publication record by any
standards.” (Vol. 394, p604, 1998)
“...we are particularly impressed with Singapore’s
commitment to supporting technoentrepreneurship, and the city state’s outstanding
Institute of Molecular and Cell Biology”
(Vol. 399, p177,1999).
… and the $10,000 note
Anthony Buss.
For the new set up, Glaxo contributed $20 million,
IMCB offered $10 million in infrastructure and research
support, while EDB matched it with another $10
million. This cross disciplinary collaboration between
industry and the Institute was the first of its kind in
Singapore, and became a working model for future
biotechnology collaborations.
The joint venture not only boosted Glaxo’s reputation
in the biomedical research community but also IMCB’s
international visibility by leading Singapore’s first major
industry-academia R&D collaboration.
This collaboration eventually spun off a drug discovery
company, MerLion Pharmaceutical Pte Ltd, in 2002.
International acclaim for IMCB
These many activities, all achieved in a short span of
time, did not go unnoticed by the international media.
Just five years after the opening of the IMCB building
on the NUS campus, Singapore was singled out by
International Business Week (Nov 1992) as one of the
strong biotechnology players among the Asian Tiger
economies.
One year later, IMCB was described by Science in a
special report on Asia as “the biology laboratory to
watch” (Vol. 262, p346), who also noted that the
quality Singapore’s R&D “compared favourably with
work in the United States.” (Vol. 262, p353-354).
The world’s highest circulated
denomination was launched in 1999
and featured a peptide sequence derived
from the proteins PTPalpha (discovered
by Catherine Pallen) and PAK1
(Ed Manser, GSK-IMCB group).
Nature, Vol 505, Byrappa Venkatesh et al., Elephant shark genome provides
unique insights into gnathostome evolution, Copyright Nature Publishing Group
(2014).
Cell Host & Microbe, Vol 4, Xu XL et al., Bacterial peptidoglycan triggers Candida
albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p, Copyright
Elsevier (2008).
Journal of Clinical Investigation, Vol 123, Al-Aidaroos AQ et al., Metastasisassociated PRL-3 induces EGFR activation and addiction in cancer cells, Copyright
American Society for Clinical Investigation (2013).
Developmental Cell, Vol 29, Jung H et al., Evolving Hox activity profiles govern
diversity in locomotor systems, Copyright Elsevier (2014).
20
Building Research capabilities
Training and education
By the 1990s, IMCB was a hive of activity across
multiple disciplines. One of its early achievements
was the complete sequencing of the dengue virus
type I (Singapore Strain S275/90) in 1992. A human
monoclonal antibody fragment against the dengue
virus was subsequently produced, which could be used
in dengue diagnosis as well as in passive immunisation
against dengue infection.
By 1997, the institute housed 160 post-doctoral
researchers and 90 BSc/MSc scientists. The priority was
always the training of Singaporean PhDs.
1998 saw the establishment of a specific-pathogenfree (SPF) animal facility at IMCB, and the successful
generation of the first knockout mice. By the end of
the decade, IMCB had established itself as a national
centre of excellence for biomedical research, as well as
an international player in the areas of cell regulation,
signal transduction and developmental biology.
IMCB’s first in-house PhD student graduated in
1990. In response to the need for postgraduates
with cross-disciplinary skills, in 1991 IMCB initiated a
comprehensive program of graduate courses for its
PhD students. These courses covered topics in nucleic
acid chemistry, developmental biology, cell cycle
regulation, human diseases, functional genomics, and
signal transduction. As a result of its open door policy,
PhD students from NUS, NUH and Singapore General
Hospital (SGH) also elected to enroll. As a result NUS
also began running its own postgraduate courses in
biomedicine, and eventually set up an NUS graduate
school (NGS).
Joint NZ-Singapore Cancer Symposium 2009 Speakers
“Hedgehog Signalling in Development, Evolution and Disease” conference
organized by Philip Ingham International leadership
Today it is taken for granted that Singapore hosts
many important Biomedical meetings, but this was
not always so. The IMCB began to focus on bringing
scientists together to promote Singapore science. In
1992 this began with an international conference jointly
organized with the Society of Chinese Bioscientists,
which attracted 800 scientists from around the world
to Singapore.
The Institute went on to found the Asia Pacific Society
of Bioscientists in 1993 and hosted the first of many
“Asia Pacific Society of Bioscientists Symposia”. IMCB
also established a Hot Spring Life Sciences Symposium
series, first in Shanghai (1995) and then Singapore
(1996).
Second Hot Spring Life Sciences Symposium, 1996
In 1998, the Asia-Pacific International Molecular
Biology Network (A-IMBN) was set up in Singapore,
with member countries spanning all of Asia. The
organization is loosely modeled on the European
Molecular Biology Organization (EMBO), with which it
maintains strong links. It is recognized as a priority APEC
initiative since 1998. In 1999 the IMCB and A-IMBN
hosted and organised the Second A-IMBN Conference.
The Gordon Research Conference (GRC) organization
is recognised internationally not only for its high quality
IMCB Staff 1992
21
of science but also for its association with ski resorts. It
was therefore of some surprise that in 1999 the GRC
leadership endorsed a proposal from the GSK-IMCB
group to host the first meeting on “Mechanisms of Cell
Signalling – G-Proteins” in Singapore. This meeting
ran successfully for 20 years, alternating between
Europe and Asia. Other notable symposia organized
by IMCB included the Euro Gold in 2009, which
highlighted EMBO Gold medalists from 1998 – 2008;
The Joint NZ-Singapore Cancer Symposium in 2009;
The 5th International Epithelial Mesenchymal Transition
Meeting in 2011; and Hedgehog 2012.
“
Science
is a broadly
international
activity. Through
IMCB in ten short
years, Singapore
has taken its place
as a significant
contributor to the
great edifice of modern biomedical science.
This science provides both cultural enrichment
for the world and an economic base for
future development.
”
– Nobel Laureate David Baltimore, President of
the California Institute of Technology at an address
commemorating 10 years of the IMCB building.
22
23
A Sign of
Things to Come
T
he year 2000 was a busy time for IMCB, with
the expansion of the Institute, the conferring
of a prestigious award and several scientific
breakthroughs.
The award ceremony on 8 June 2000 was attended
by Lee Kuan Yew, then Senior Minister, IMCB Director
Chris Tan and Philip Yeo, Chairman of the IMCB
management board.
That year, the new 4,000 sq m IMCB Annex (now
the Brenner Building), was completed to allow the
comfortable addition of new research groups and a
temporary location for the fledgling BioInformatics
Institute (BII) under Gunaretnam Rajagopal.
In 2006 Philip Yeo, the founding Chairman of A*STAR,
was conferred the same honour.
“
IMCB and Annex Building
The vibrant growth of the Singapore Institute serves as an important example for
those in charge of promoting scientific and technological activities in Japan.
- commentary by Nihon Keizai Shimbun
The 5th Nikkei Asia Prize
As a testament to the
impact of IMCB over
the years, Nihon Keizai
Shimbun conferred the
5th Nikkei Asia Prize
to IMCB in 2000 for
outstanding research in
biological sciences. IMCB
won in the category of
Technology
Innovation
which recognizes the
achievements of people
and organizations that
have improved the lives of
people throughout Asia.
The awards were created
and presented by Nikkei
Inc, one of the largest
media corporations in
Japan.
”
A milestone in the era of genomics
The year 2000 also saw IMCB and the Joint Genome
Institute (JGI) of the United States Department of
Energy (DOE) form a consortium to sequence the
fugu (pufferfish or Takifugu rubripes) genome. The
International Fugu Genome Consortium represented
one of the largest international genome- sequencing
projects since the historic Human Genome Project. The
goal of the consortium was to sequence, assemble,
annotate, and ultimately complete the fugu genome,
and disseminate the information to the greater research
community.
Two years later, the Consortium completed a draft
sequence of the fugu genome. This was a significant
feat as it was the first vertebrate genome to reach this
level of completion next to the human genome. The
genome sequence was published in Science.
“
”
The most significant investments
are in the Biomedical Sciences. After 15
years, the Institute of Molecular and Cell
Biology (IMCB) has gathered over 200
scientists, 80% from overseas. They have
made the IMCB into a leading intellectual
hot-house for the Biomedical Sciences in
Asia.
- Speech by then Senior Minister Lee Kuan Yew
At The Forbes Global CEO Conference Gala Dinner
on Wednesday, 19 September 2001.
“
I have been very pleased to be part of
the Scientific Advisory Board of the IMCB. It has
given me a double joy: making many new friends
and seeing first- hand the remarkable results of
a remarkable experiment. In 10 years IMCB has
moved from a dream to becoming one of the
foremost institutes of basic biomedical research.
It can match most of the better centres in the
West, and it is already.
The Nikkei Award
”
– Robert Gallo co-discoverer of HIV, talking at the 10th anniversary of the IMCB building.
24
From the Fish Tank
to the Open Seas
A
t the turn of the millennium, IMCB found
itself at the crossroads. While the successes
it had achieved clearly signalled that it was
headed in the right direction, there were
nationwide changes afoot.
A budget of $1.48 billion had been set aside for the
new biomedical sciences (BMS) initiative, underscoring
the government’s commitment to the cause. The NSTB
was renamed A*STAR and with enthusiastic partners,
including the BMRC Executive Director Louis Lim,
Philip Yeo pushed for the immediate construction of
a Biomedical hub at Buona Vista, that became the
“Biopolis” The significant investment in buildings
to house research institutes was aimed at attracting
more industries to the biotechnology hub. What would
IMCB’s place be in this drastically changed landscape?
and many colourful collaborators in other disciplines,
as well as exotic species belonging to big Pharma.
Familiarity through more than a decade of industry
collaborations, and its involvement with the newer
institutes (e.g. National Cancer Centre and BTI) allowed
IMCB to comfortably leverage on the synergy that
Biopolis afforded.
All Institutes now have an open door policy when it
comes to the use of specialist facilities, in order to
maximise the use of resources. Newest joint efforts
include the IMCB-IMB (Institute of Medical Biology)
Electron Microscopy Suite, an A*STAR collaborative
effort at Biopolis to share expertise and resources
paving the way for future collaborations. Likewise the
world class IMCB zebrafish facility at Proteos level 8
now supports the entire Biopolis community.
The move from the NUS campus to Biopolis was not
only a symbolic one. Going from the “fish tank” of a
single Institute to the “open seas” provided exposure
SARS test kit
2003
A strong response to SARS
Just as the Institute was preparing for its move to
Biopolis, urgent matters of an international nature took
centre stage.
Severe Acute Respiratory Syndrome (SARS) first reached
Singapore in late February 2003 with the return of
three Singaporean women from Hong Kong, where
they had caught the virus at their hotel. They were
all hospitalised on return for pneumonia; interestingly
only one of the patients sparked the outbreak of SARS
in Singapore. The Infectious Diseases Act was invoked
on the 24 March to quarantine all contacts.
Racing against time, IMCB researchers worked with
Genelabs Diagnostic Pte. Ltd. to develop two antibodybased tests for the diagnosis of SARS, requiring a single
drop of serum or blood. A rapid 15-minute quick test,
or a more accurate ELISA assay gave results within 1.5
hours. Both tests were based on two IMCB-developed
purified recombinant SARS-derived proteins.
By the summer of 2003 the chain of human-to-human
transmission had been broken. Doctors had the tools
Zebrafish Facility
At the individual level, a number of A*STAR researchers
including Weiping Han, Dmitry Ivanov and Bruno
Reversade hold joint appointments with IMCB.
Likening this change to the experience of an only child
becoming one of five children, IMCB Executive Director
Wanjin Hong today sees the Institute’s role as that of
the “eldest sibling” in the family.
SARS virus
25
“
This collaboration is an excellent
example of how the public and private
sectors worked together within a short
space of time to generate tools that
helped to control an important public
threat like SARS.
– Wanjin Hong
”
to identify exactly who was infected with the virus,
and what precautions to take to avoid passing it on.
Nonetheless during this period a total of 238 people
were infected in Singapore, with 33 deaths.
These experiences highlight the need for both stateof-the-art research in communicable diseases, and
substantial public health capacities. A new National
Centre for Infectious Disease, with about 300 beds,
will be opened at Tan Tock Seng Hospital by mid-2018.
The work on SARS at IMCB, which was overseen by
Wanjin Hong, involved two key groups lead by Yee
Joo Tan and Masafumi Inoue. In appreciation of these
achievements IMCB was given a President’s Certificate
of Commendation in October 2003 for combating and
containing SARS.
26
Nancy Jenkins
David Lane
Philip Ingham
A Shark and several Whales
In it for the long haul
In the years following the move to Biopolis IMCB
continued to produce world class research, although
questions arose as to how these findings could be best
exploited.
Returning to the helm at IMCB in 2011, Wanjin
Hong continued the drive to stimulate more industry
engagement, and establish team-based impactful
research. One of his first actions as Executive Director
was to streamline the research groups into two
distinct tracks: the Discovery Research Division and
the Infrastructure, Technology & Translational Division
(ITTD).
Under the leadership of David Lane, the Executive
Director from 2004-2007, the Institute strengthened
its focus on translational research. David Lane helped
to raise the scientific profile of IMCB by recruiting
international leaders including Neal Copeland and
Nancy Jenkins from the USA, Philip Ingham from
the UK and Jean Paul Thiery from France. At the
same time, he set about establishing the A*STAR
Experimental Therapeutics Centre (ETC) to accelerate
drug development in Biopolis itself.
In 2007 IMCB secured ~US$5 million from The
National Human Genome Research Institute
(NHGRI) for the whole genome sequencing of
the elephant shark. The same team previously
led the international consortium that
successfully completed the pufferfish genome
in 2002.
➣Jean Paul Thiery
Pernille Rørth
Stephen Cohen
Neal Copeland
In 2007 Neal Copeland was appointed Executive
Director of IMCB. During his tenure he sought
to streamline operations at IMCB but carried
on the task of recruiting the brightest and best.
This included renowned Drosophila geneticists
Stephen Cohen and Pernille Rørth who were
previously in Temasek Lifescience Laboratories.
When Neal Copeland decided to leave in 2010,
Stephen Cohen was appointed as acting Executive
Director to navigate IMCB into the current 20112015 funding cycle. Cohen played a pivotal role in
the development of the A*STAR Advanced Molecular
Pathology Laboratory (AMPL) and to further IMCB’s
engagement with industry.
27
In order to align with A*STAR’s mission,
the ITTD provides infrastructural support
to scientists both within and external to
the Institute. It helps to drive translational
research, and promotes collaborations with
clinicians and industry partners.
Wanjin Hong sees younger scientists as
a central focus of his mission, keeping in
mind that these individuals have a stake
in Singapore’s success, and will make the
long-term impact needed by society. In
particular, he conceptualised the IMCB
Junior Investigator (IJI) programme to
nurture returning A*STAR scholars as well as
exceptional young post-doctoral scientists.
As IMCB celebrates its 30 anniversary,
Wanjin Hong is preparing the Institute for
future challenges by focusing on areas of research that
have inherent translational potential. He notes that
“collaborations and sharing of our facilities lead to
both cost savings and benefits for the larger scientific
community.”
th
“
I am shaping IMCB
to focus on human disease
pathways and discovery
research with translational
potential and industry interest,
while maintaining a vibrant
and conducive research culture
to attract and retain young
and capable talent.”
– Wanjin Hong
”
28
29
Personal
Perspectives
Reflections by:
1.
Sydney Brenner
2. Wanjin Hong
3. Chris Tan
Introduction
4. Louis Lim
5. Philip Yeo
6. Pin Lim
7.
Richard Sykes
Immuno-staining of the Golgi apparatus.
Image: Elsa Ng, sGSK lab
IMCB is the collective achievement of many eminent scientists and
policy makers who shared a vision of its potential, as well as the
individual Principal Investigators and researchers who turned their
vision into reality. These first-hand accounts of IMCB’s journey give a
unique perspective to the challenges that the Institute faced and how
they were overcome.
30
Sydney Brenner
31
Wanjin Hong
On the importance of IMCB:
“I stressed to both Philip [Yeo] and the NSTB that the
only way that biomedical research and commercial
spin-offs from such research could evolve and prosper
in Singapore was by establishing a single agency that
oversaw all biomedical research, from molecules to
mind—and nothing else.”
On the ethos of research:
“In science, we are always working in the future. If
you only work in the present, it’s very boring; we must
always strive to do something really new.”
S
ydney Brenner, who received the 2002 Nobel
Prize in Physiology or Medicine, is hailed as a
pioneer of molecular biology for unraveling
the triplet code of messenger RNA, and the
“father of the worm” for establishing C. elegans as a
model to study programmed cell death.
Brenner was associated with IMCB since its foundation,
and can be credited with molding it into the worldclass institution that it is today. He served as founding
chairman of the IMCB Scientific Advisory Board from
1985 to 1995. His team at IMCB published the fugu
(pufferfish) genome in Science.
For his contributions to the development of life sciences
in Singapore, Brenner received the 2000 Distinguished
Friends of Singapore award and the title of Honorary
Citizen of Singapore in 2003.
On the virtue of impatience:
“This is one of the great things I have come to realise
about Singapore; that they are impatient and everything
must be done yesterday—not today, but yesterday. It is
very stimulating—and it actually produces results.”
On the prospects for Singapore:
“I’m deeply impressed with the spirit of young
Singaporeans I’ve worked with and believe that their
attitude bodes well for the future of Singapore.”
Clockwise from left: Wanjin Hong, Andrew McMahon, Neal Copleand and Nancy Jenkins
W
anjin Hong has been the Executive
Director of IMCB since 2011. He
joined IMCB as a Principal Investigator
in 1989, and won the National Science
Award (Singapore) in 1999 for helping to discover
about half of mammalian SNAREs.
As acting Director of IMCB from 2001-2004, he oversaw
several milestones in IMCB history, including IMCB’s
merger with IMA and its relocation to Biopolis. Under
his leadership, IMCB was awarded a 2003 National Day
Award for combating and containing SARS.
In recent years, Hong has helped IMCB transition into a
new phase that combines both basic and translational
research. He is also preparing for the next generation
of leaders with training programmes for junior PIs. In
2014, Hong received the Public Administration Medal
(Silver) for his contributions to biomedical research in
Singapore.
On what made IMCB the natural choice:
“The decision was simple for me and based only on
one criterion: if I went to IMCB, would my research
done there be internationally competitive?”
On the challenges of the early days:
“There was no internet or email; the only thing available
was the fax machine. Back then, even telephone calls
were very expensive. Plus, Singapore was far off from
the main campuses of US and Europe. We were very
isolated, and there was no culture of research here
yet.”
On his decision to serve as Executive Director:
“I decided to stand for the position of ED as I felt that
the lack of long-term leadership would be detrimental
to the institute.”
On what makes IMCB outstanding:
“Our strengths are our dynamic and adaptive people,
who have been able to change their mind-sets
accordingly with A*STAR’s evolving mission.”
On what’s next for IMCB:
“I am shaping IMCB to focus on human disease
pathways and discovery research with translational
potential and industry interest, while maintaining a
vibrant and conducive research culture to attract and
retain young, capable talent.”
32
Chris Tan
33
Louis Lim
On his role in founding the BMS sector in Singapore:
“The experience of being part of the pioneering
team to build the BMS R&D sector and to see how
it has developed and advanced today, has been truly
rewarding for me.
Ming Kian Teo of NSTB and Chris Tan
C
hris Tan was the founding director of IMCB
(1985-2001). His seminal work on the antiviral protein interferon included its largescale purification for anti-cancer trials (Cross
Cancer Center 1978-80). In 1983, while working at
the University of Calgary, he was invited by Goh Keng
Swee to found IMCB.
By the end of his tenure, IMCB became an international
success story inspiring Singapore and the region to
focus on biomedical research. The first and second
generation alumni of IMCB, nurtured by Chris Tan, are
now international science leaders based in Singapore
and abroad.
For his contributions to the biomedical sector in
Singapore, Tan received the National Science and
Technology Medal in 1993, and the Public Service
Administration Medal (Gold) in 2001.
On the founder generation:
“The establishment of IMCB owes much to the
contribution of many people. In particular I thank Goh
Keng Swee for his role in catalysing the birth of the
Institute, Tony Tan Keng Yam, Pin Lim, Philip Yeo, Sydney
Brenner, members of the Advisory Board, members of
the Advisory Committee and friends of IMCB for their
continued support, advice and encouragement.”
On Singapore’s research environment:
“There are already many pockets of excellence within
Singapore. I have already encountered remarkable
and unstinting support, well-founded optimism and
immense co-operation from scientists, clinicians and
government leaders.”
Members of 1999 SAB Top Louis Lim, Robert Gallo, Robin Weiss, Tony
Pawson Bottom Sydney Brenner, Chris Tan, Alice Huang, Suzanne Cory, David
Baltimore, Chor Chuan Tan
On success in biotechnology:
“Success in biotechnology will depend on the
combination of the basic research effort and of a
critical mass of outstanding scientists, with the skills of
businessmen and knowledgeable administrators.”
The commitment by Singapore:
“lMCB was a bold experiment to see if a city state could
become a significant player in scientific discoveries.
By 1993 it was evident that the lMCB had become
an international success story. Singapore has broken
through the ‘discovery barrier’. This teaches a lesson,
that a small country can make important scientific
contributions to the world so long as it is committed
to do so.”
On IMCB’s accomplishments to date:
“By the first 15 years of IMCB’s establishment, the
impact of its research in cell signalling, transport and
development was well acknowledged. Today, IMCB
alumni and associates have assumed key leadership
positions, in Singapore, in China and in the Asia-Pacific.
Together, they have provided a network and capability
for Singapore to build a viable biomedical healthcare
industry emanating from Asia.”
L
ouis Lim, from the INL, was involved in the
founding of IMCB as a member of IMCB’s
Scientific Advisory Board since 1984. Louis Lim
made several significant scientific contributions
including his early discovery of poly(A) in mammalian
messenger RNA, and the use of recombinant DNA
technology to study brain expressed genes. He was
rooted in Singapore as head of the Glaxo-IMCB
laboratory from 1989-2009.
He has played a very senior role in the biomedical sector
in Singapore, serving as a member of the International
Advisory Panel of the National Neuroscience Institute
(1995-1998) as well as on the International Panel of
Advisors for the Singapore Science Council (19861990) and the National Biotechnology Committee
(1995-1999).
He was the founding director of the A*STAR BMRC
from 2000-2002, where he worked very closely with
A*STAR Chairman Philip Yeo to develop the BMS
initiative in its first phase.
On translational focus:
“I also saw a very systematic strategy in Phase II of
putting in place a translational focus beyond basic
research. The work for Biopolis very quickly expanded
from developmental studies using the yeast, fugu fish
and drosophila as models to stem cell research, tissue
engineering and bioimaging.”
On training researchers at A*STAR:
“Talent was central to the strategy. Even in 2001, there
was a very bold vision of training 1,000 local PhD talents
to support Singapore’s foray into a knowledge based
economy. Looking at the international recognition that
we have gained for the tremendous quality of science
and talent, the investment made over the last decade
has truly been worthwhile.”
On his hopes for IMCB:
“I am most proud of the young team and the research
systems that I had put in place at BMRC, the many
young to mid-level researchers whom I had nurtured
and trained through the Glaxo- IMCB lab, including
Edward Manser and others. In the next ten years, I
hope to see a new generation of research leaders from
the talent that Singapore has nurtured.”
34
Philip Yeo
35
Pin Lim
Philip Yeo, Pin Lim and Chris Tan
P
hilip Yeo, Chairman of SPRING Singapore,
is widely acknowledged for spearheading
the biomedical sector in Singapore, First as
Chairman of EDB from 1986-2000 and then
as Chairman of A*STAR from 2000-2009. He was also
special advisor for economic development in the Prime
Minister’s Office from 2007-2011. His long association
with IMCB includes that as Chairman of the IMCB
Management Board from 1998 to 2000.
On starting from scratch:
“We knew it was important for a small and resourceless
country like Singapore to develop our capabilities in [the
life sciences]. But how to start and where to begin? Few
places in Asia had an endogenous research base for
building an industry highly dependent on knowledge
and IP. We knew this was a discovery intensive industry
and a vehicle was required to undertake the first step
of establishing a research culture and the culture of
making discoveries.”
Yeo was the driving force behind establishing Biopolis
and Fusionopolis, where he continued to recruit both
renowned scientists and leading bio-pharma companies
to Singapore. He has developed a talent pool of more
than 1,000 young Singapore scientists for A*STAR.
On IMCB’s successes:
“Singapore has established itself in the world of
biological science and IMCB has become an international
landmark for science and discovery located in the
heart of the Asia Pacific.” – 2000 message as IMCB
Management Board Chairman
In 2006, Yeo received Singapore’s most prestigious
National Day Award, the Order of Nila Utama (First
Class), for his contributions to Singapore.
On recruiting the best talent:
“I was in the kidnapping business. There’s an old
Chinese saying that the bandit chief looks for the rich
people, you don’t go for the poor ones. In that vein,
I took the time to study the quality and quantity of a
person’s publications to figure out who to recruit.”
His advice to Louis Lim:
“I told Louis, ‘Bring 50 scientists a year. There are 52
weeks, so you can take a two-week holiday.’”
P
in Lim is the longest serving Vice Chancellor
of the NUS. From 1981-2000, he oversaw the
growth of NUS from its infancy to one that
was a leader in medical and basic research,
widely recognised for teaching excellence and strong
academic achievement worldwide.
Pin Lim first started his career at the University of
Singapore in 1966 as lecturer and was later promoted
to Professor, heading the Department of Medicine.
He is currently University Professor at the Yong Loo
Lin School of Medicine, NUS as well as Emeritus and
Senior Consultant at the Endocrinology Department of
the NUH.
Pin Lim was instrumental in securing the initial
funding required to establish IMCB. In addition, he
also supported and managed the staff of IMCB in his
capacity as Vice Chancellor of NUS.
1985 as a turning point in Singapore science:
“The establishment of IMCB was very much part of the
development of science and research in Singapore; it
was in fact a landmark.”
On early challenges:
“When I first joined the university in the 1960s, I was
told that the whole university had a research budget of
$20,000 a year.”
On IMCB’s growth over three decades:
“It was like a crystal - once we were able to get
nucleation, it grew very nicely.”
On IMCB’s impact:
“IMCB has done a lot of good work on topics like
aging, cancer and diabetes. Beyond that, it helped to
establish a strong research culture on the campus and
for Singapore as a whole. It has been a focal point to
attract more good people to come; once you've got
that, to set up another new institute is no big deal.”
36
37
Richard Sykes
Miranda Yap, Vijay Mehta, Philip Yeo, Richard Sykes, Chee Wee Goh, Chris Tan and Hsing Hua Huang at the official opening of CNPR
R
ichard Sykes was Chairman of Glaxo Plc from
1993-2002 . He was elected a Fellow of the
Royal Society in 1997 in part for his work on
β-lactamases, and the discovery of the first
monocyclic β-lactam antibiotic, aztreonam.
In 1992, he led a team to Singapore to discuss a project
on high throughput screening for active molecules in
natural products, which led to the establishment of the
CNPR at IMCB.
Richard Sykes in subsequent years became deeply
involved with science policy and biomedical science
development both in Singapore and the UK. He has
served as Chairman of Singapore International Advisory
Panel for Biomedical Science since 2000. From 20012008, Sykes was the Rector of Imperial College London.
On how Glaxo got involved:
“In 1986, I became the R&D director for Glaxo. The
company had invested heavily in manufacturing
in Singapore and I was looking to invest in research
projects. Together with Chris Tan and EDB, we decided
to invest in natural products research.”
On the challenges of the early days:
“The biggest challenge was appointing top class
scientists from around the world. I remember this being
managed by Philip Yeo and Sydney Brenner.”
On IMCB’s impact in the past three decades:
“As one of the first institutes to be set up in Singapore,
it has been instrumental in leading the way and
attracting top class scientists who have then gone on
to work in other institutes. IMCB has been a flagship
for biomedical research in Singapore.”
On his hopes for IMCB in the years to come:
“The research and development scene in Singapore is
a constantly changing environment, but I still see IMCB
having a significant impact on social and economic
development, in whatever form it may take in the next
30 years.”
On his first visit to IMCB
“in fact walking around the building with Chris Tan,
we came across a sleeping python under some building
materials. That is the only snake I have ever seen in all
my visits to Singapore over the past 26 years. “
World-Class
Research
1.
Infectious Diseases: Know the enemy
2. Cancer: The enemy within
3. Development: How did we get here?
4. Genomics: Where do we come from?
5. Structural Biology: Form begets function
6. Cell & Molecular Biology: Understanding the
building blocks of life
7.
Cell Signalling: Sending the right message
8. New Technologies: Bringing it first to Singapore
9. Continuing Scientific Excellence: Hot off the press
A coronal section across an E13.5 mouse embryonic brain and stained with antibodies against Sox2 (red),
bIII-tubulin (green) and DAPI (blue). Image: Shuhui Lim and Philipp Kaldis
38
Infectious Diseases:
Know the enemy
A
ccording to the widely misused volume
“The Art of War” by Sun Tzu, knowing
your enemy is the key to success in battle.
While science has failed to moderate
human intolerance for their neighbours, much more
progress has been made in the war on infectious
diseases. Time and again it has been demonstrated
that a deep understanding of pathogens underscores
the development of effective treatments.
Whether they be viruses, bacteria or fungi, IMCB
scientists have closely studied these enemies, sequenced
their genomes and come up with innovative ways to
detect, disrupt and disarm the unwelcome invaders.
Detecting viruses
Viruses are too small to be seen under the microscope,
yet many are devastating. The human papillomavirus
(HPV) is now well known as a causative agent for
cervical cancer. In 1987, when the link between HPV and
cervical cancer was just beginning to be established, a
group of IMCB researchers led by Hans-Ulrich Bernard
uncovered a key link between circulating hormones
and viral gene transcription1. Focusing on the most
clinically-relevant strain, HPV-16, the team found DNA
sequences which allow viruses to be regulated by
endogenous hormones. Their work established how
viruses can hijack common physiological processes and
cellular transcription factors for their own ends, and
has been validated in many other human viruses.
In 1992, IMCB researchers were the first to complete the
sequencing of the dengue virus type I (Singapore strain
S275/90), the predominant serotype in Singapore2.
Their patented work enabled the development of a
monoclonal antibody fragment against dengue with
use in diagnosis or treatment. Today, the sequence
analysis of new Dengue variants is the first stage in
fighting the disease.
Disrupting bacterial communication
For single-celled bacteria there is strength in numbers.
Quorum sensing (QS) is a community regulatory
mechanism used by bacteria to synchronize their
behaviour. Acting as a collective confers a competitive
advantage, allowing them to behave like a multicellular
organism.
This
process
promotes
virulence,
and understanding the molecular mechanisms
underpinning QS is key to understand microbial ecology
and pathogenesis. The need for new antibiotics is well
publicized and QS represents a different Achilles’ heel.
Lian Hui Zhang has made significant contributions
understanding QS by being one of the first to uncover
key signalling molecules and regulatory networks3. His
team identified methyl dodecenoic acid as a diffusible
signal factor that regulates virulence and biofilm
dispersal in the bacterium Xanthomonas campestris.
This DSF signalling pathway has been worked out from
detection of the signal to the activation of transcription
factors.
Reasoning that the ability to disrupt the QS signalling
would confer a competitive advantage—a strategy
now known as “quorum quenching”— Zhang’s group
studied organisms known to interact with bacteria
and found two enzymes capable of degrading QS
signals: AHL-lactonase and AHL-acylase3. These natural
enzymes are the proof that interfering with QS can
control bacterial infections.
Disarming opportunistic invaders
Fungal infection by Candida albicans is prevalent in the
population but becomes deadly in sick and immunocompromised patients. It ranks among the top four
hospital-acquired infections of the blood, with a
mortality rate as high as 45 percent.
The human body has evolved numerous intrinsic
defence mechanisms against blood infections including
sequestering iron, an essential nutrient for pathogens
to survive. Yue Wang’s group discovered that C.
albicans can circumvent this by using a high-affinity
iron transport protein called CaFtr14 to suck iron out of
blood. Without this protein C. albicans cannot cause
infection.
Among the many discoveries of Wang’s group they
have uncovered the molecular mechanisms that
control the transition of C. albicans to an invasive
and elongated hyphal form of the fungus. In 2004,
they found a key regulator of this process called
Hgc1, which talks to the master cell cycle regulatory
kinase Cdc285. This has lead to finding other central
components that control growth of C. albicans that are
direct substrates of the Hgc1-Cdc28 kinase complex .
For these multiple ground breaking discoveries in the
biology of C. albicans, Wang Yue was awarded the
President’s Science Award in 2012.
Highlighted papers:
1. Gloss, B., Bernard, H. U., Seedorf, K. and Klock, G.
(1987). The upstream regulatory region of the
human papilloma virus-16 contains an E2 proteinindependent enhancer which is specific for cervical
carcinoma cells and regulated by glucocorticoid
hormones. EMBO J. 6(12), 3735-3743.
2. Fu, J., Tan, B., Yap, E., Chan, Y. and Tan, Y. (1992).
Full-length cDNA sequence of dengue type 1 virus
(Singapore strain S275/90). Virol. 188(2), 953-958.
3. Dong, Y., Wang, L., Xu, J., Zhang, H., Zhang, X. and
Zhang, L. (2001). Quenching quorum-sensingdependent bacterial infection by an N-acyl
homoserine lactonase. Nature 411, 813-817.
4. Ramanan, N. and Wang, Y. (2000). A high-affinity
iron permease essential for Candida albicans
virulence. Science 288:1062-1064.
5. Zheng, X., Wang, Y. and Wang, Y. (2004). Hgc1,
a novel hypha-specific G1 cyclin-related protein
regulates Candida albicans hyphal morphogenesis.
EMBO J. 23, 1845-1856.
Septin localization in Candida albicans. Image: Yanming Wang
39
40
Cancer:
The enemy within
C
ancer, a disease of uncontrolled proliferation
of cells is still a major killer and in spite
of remarkable advances in discovery and
healthcare many cancers ultimately resist
treatment.
Over the years, IMCB researchers have built up an
impressive body of work detailing the molecular
mechanisms and genetic landscape linked to various
cancers. Their work has deepened our understanding of
how cancers initiate and progress and what potential
therapeutic measures can be developed.
How cancer cells resist death signals
It is now believed that most pre-cancerous cells are
eliminated long before they can be detected by
programmed cell death or apoptosis. IMCB scientists
discovered that defects in apoptosis exist in the
commonly studied human breast cancer cell line MCF7, and indeed may other types of cancer cells. In what is
now a landmark paper1, Alan Porter’s group uncovered
the role of the master regulator caspase-3 in cell death.
Porter and his team noticed that MCF-7 cells, a breast
cancer cell line, did not produce functional caspase-3.
Using some genetic sleuthing, they made the surprising
finding that MCF-7 cells only produced a mutated
caspase-3 mRNA. When these MCF-7 cells are treated
with agents that should lead to the death program,
they fail to die. They found that caspase-3 is required
for DNA fragmentation - which is the irreversible step
in apoptosis.
The group’s paper in the Journal of Biological Chemistry
is a highly cited paper in basic science in Singapore
- having been cited more than 1,400 times. For his
outstanding contributions to understanding the role of
caspases in cell death, Porter won the National Science
Award in 2004.
Another link between apoptosis and colorectal cancer
was discovered at IMCB. Dmitry Bulavin’s team found
that the lack of Wip-1 helps mice resist colorectal
cancer. This absence of Wip-1 hyper-activated the
tumour suppressor p53 (discovered by David Lane),
causing cancer stem cells to undergo apoptosis and
thereby preventing tumours from forming2.
Protein phosphatases are important in cancer
Many cancers are initiated because of inappropriate
activation of receptor tyrosine kinases. Protein tyrosine
phosphatases (PTP) are enzymes that antagonize
tyrosine kinases and are therefore expected to be
tumour suppressors. In 1992, Pallen and her team were
the first to establish that remarkably PTPalpha can act
as an oncogene3, because it is actually able to keep the
typosine kinase Src kinase in an active state.
In 1998, Qi Zeng and her team discovered that PRL-3,
another PTP, was at high levels in many different cancer
cells. These cells often show increased epidermal
growth factor receptor (EGFR) activity, a pathway well
known to be associated with breast and lung cancers.
The elevated PRL-3 causes an “addiction” of the cancer
cells to EGFR for their survival4. Zeng has proposed
and demonstrated that elevated PRL-3 is a predictive
marker for therapeutic response in a clinical study
conducted in collaboration with the National University
Health System.
Zeng was awarded a Flagship grant by Exploit
Technologies Pte Ltd (A*STAR) to pursue a new way
of tackling cancers with elevated PRL. Remarkably
monoclonal antibodies (Mab) directed to PRL-1 or PRL3 can get into cells and inhibit metastasis (migration
of tumour cells around the body). This finding has
tremendous potential for a host of Mab therapies.
Using viruses to discover oncogenes
Viruses, particularly those that integrate into genomic
DNA, and affect the transcription of many key
proteins, generate tumours by multiple mechanisms.
For example, hepatocellular carcinoma (HCC) is
driven by hepatitis B virus (HBV) infection. Which of
the many mutations drive HCC? Undeterred by the
complexity, a team of scientists led by Nancy Jenkins
Human hepatocytes (Green) grown in mouse liver. Image: Qingfeng Chen
and Neal Copeland began to map out the defective
genetic landscape of HCC5. Using a transposon-based
mutagenic approach, they identified 21 genes involved
in the early stages of HCC and 2,860 genes thought
to play a role in the later stages. Interestingly, a large
number of genes linked to cellular metabolic processes
were uncovered, confirming the “Warburg effect” in
these tumours.
Cell division control networks and cancer
At a fundamental level all cancers have one characteristic
in common, uncontrolled proliferation. For this reason
IMCB scientists have studied many control circuits
underlying the cell division machinery. This network is
so fundamental to life that the machinery is conserved
across yeast, flies, mice and humans.
Uttam Surana’s group has been studying the
basic nature of a set of surveillance circuits called
“checkpoints” that ensure the proper order of events
during cell division. In many cancer cells these circuits
are defective, causing cells to divide out of control, but
this is also one of their key weakness.
Using yeast as a model system, Surana’s team has
found for the first time that the mitotic spindle, a
highly organized assembly of microtubules responsible
for distributing chromosomes equally into daughter
cells, is an important target of the checkpoint controls6
that sense problems with chromosome duplication or
detect chromosome damage. The checkpoints prevent
premature chromosome movements and maintain
the integrity of the genome. For his outstanding
contribution to the understanding of control circuitry
that governs cell division, Surana won the National
Science Award in 2007.
41
The cyclin dependent kinases (CDKs) are the key
drivers of networks of the cell division machinery.
Among various Cdks, Cdk1 is essential for embryonic
development. Philipp Kaldis’s team has been
investigating the tissue-specific roles of Cdks in
mammals using mouse as a model system. Using
gene ablation in mouse, Kaldis’ group showed7 that
Cdk1 ablation is surprisingly well tolerated by the liver
and that Cdk1-deficient liver cells can divide normally
during liver regeneration. Unexpectedly, the loss of
Cdk1 makes the liver completely resistant to tumour
formation induced by activation of oncogene RAS or
by inactivation for the tumour suppressor p53. This is
an important finding indicating the potential of Cdk1
inhibitors as therapeutic agents in specific contexts.
Highlighted papers:
1. Janicke, R., Sprengart, M., Wati, M. and Porter, A.
(1998). Caspase-3 is required for DNA fragmentation
and morphological changes associated with apoptosis. J.
Biol. Chem. 273, 9357-9360.
2. Demidov, O., Timofee, O., Lwin, N., Kek, C.,
Appella, E. and Bulavin, D. (2007). Wip1 phosphatase
regulates p53-dependent apoptosis of stem cells and
tumorigenesis in the mouse intestine. Cell Stem Cell 1:180190.
3. Zheng, X., Wang, Y. and Pallen, C. (1992). Cell
transformation and activation of pp60c-src by
overexpression of a protein tyrosine phosphatase. Nature
359, 336-339.
4. Al-Aidaroos, A., Yuen, H., Guo, K., Zhang, S.,
Chung, T., Chng, W. and Zeng, Q. (2013). Metastasis
associated PRL-3 induces EGFR activation and addiction in
cancer cells. J. Clin. Invest. 123(8), 3459-3471.
5. Bard-Chapeau, E., Nguyen, A., Rust, A., Sayadi, A.,
Lee, P., Chua, B., New, L., de Jong, J., Ward, J.,
Chin, C., Chew, V., Toh, H., Abastado, J., Benoukraf,
T., Soong, R., Bard, F., Dupuy, A., Johnson, R.,
Radda, G., Chan, E., Wessels, L., Adams, D., Jenkins,
N. and Copeland, N. (2014). Transposon mutagenesis
identifies genes driving hepatocellular carcinoma in a
chronic hepatitis B mouse model. Nat. Gen. 46, 24-32.
6. Krishnan V., Nirantar S., Crasta K., Cheng A. Y. H.
and Surana U. (2004). DNA-Replication Checkpoint
prevents precocious chromosome segregation by
regulating spindle dynamics. Mol. Cell 16:687-700
7. Diril M.K., Ratnakaram C.K., Padmakumar V.C., Du
T., Wasser M., Coppola V., Tessarollo L. and Kaldis
P.R. (2012). Cyclin-dependent kinase 1 (Cdk1) is essential
for cell division and suppression of DNA re-replication but
not for liver regeneration. Proc Natl Acad Sci USA
109:3826-3831.
42
Development:
How did we get here?
W
ith their relatively short life spans and
comparatively simpler genomes, model
organisms have made fundamental
contributions to our understanding
of human health and disease. From the first few cell
divisions of the fertilized egg to the events at the end
of an organism’s life, all these can be studied by using
fruit flies, zebrafish or mice. Further, if one understands
development then cells can also be programmed in a
petri dish.
IMCB scientists have not only made seminal findings
using such model organisms, but have also pioneered
techniques to increase the power of screening for new
traits.
Brain development in fruit flies
In 1997, William Chia’s group published a paper
describing the mechanism by which embryonic neural
cells maintain the asymmetry required for proper brain
development1. They showed that two proteins—
inscuteable and staufen—interact to anchor at one end
of dividing neuroblasts so that the two resulting cells
are different. This research shed light on how, during
embryonic development, one type of stem cell can
divide to give two different daughter cells.
More recently, a team led by Stephen Cohen found that
different stem cells in the Drosophila gut are regulated
by tiny RNA molecules called microRNAs. Their study
in Genes & Development2 showed that microRNA miR305 coordinates two important signaling pathways
that are required during development, namely those
activated by insulin and Notch. This unexpected finding
helps us understand the link between nutrition and
embryo development.
Why vertebrate models matter
While studies in invertebrates have their advantages,
extrapolating the findings established from insects or
worms to humans is not without its complications. The
zebrafish (Danio rerio) may seem far from human, but
most of its tissues develop along similar lines, and are
built from the same proteins.
As a case in point, Sudipto Roy’s work on muscle
formation in zebrafish illustrates both the substantial
continuities as well as limitations of invertebrate
research3. His group characterised Kirrel, a receptor
protein known to organise muscle precursor cell
(myoblast) fusion in D. melanogaster. Their work showed
that just as in fruit flies, Kirrel is essential to generate
proper muscle in zebrafish, and demonstrated an
unanticipated evolutionary conservation.
Further dissecting the Kirrel signalling
pathway, Roy’s team identified the
GTPase Rac as the most downstream
intracellular transducer of Kirrel for
both fruit flies and zebrafish. Turning
on Rac led to the expected formation
of giant hyperfused cells in zebrafish.
However this does not work in fruit flies,
highlighting the importance of working
with vertebrates in order to understand
human development.
GFP fat fly. Image: Stephen Cohen.
1 day old zebrafish embryos expressing GFP in muscle cells. Image: Sudipto Roy
Human development in a dish
Human embryonic stem cells (hESCs) have attracted
much attention because they provide a means of
studying early human development and making
designer cells in a dish. By studying in detail how
hESCs achieved self-renewal and pluripotency, it has
been possible to develop methods to make induced
pluripotent stem cells (iPSC) from almost any type of
cell.
IMCB’s Frederic Bard, in collaboration with researchers
at the Genome Institute of Singapore (GIS) identified
two key regulators of hESCs which unlock the potential
of stem cells for new therapies4. In this study, Bard’s
team performed the first ever genome-wide study of
human stem cells using a large-scale RNA interference
screen. They found PRDM14, a transcription factor
that enhances the reprogramming of differentiated
cells into pluripotent stem cells. Surprisingly PRDM14
is not required to make mouse ESCs, which suggests
where possible, human cells should be used to study
the human condition.
Teasing out the secrets of single cells
New technologies such as high-throughput DNA
sequencing have catapulted biology into an era in
which generating, analysing and storing vast amounts
of data is a significant challenge. IMCB researchers
have not been slow to adopt such technologies, and
to use them to pose better research questions.
43
In collaboration with scientists
from A*STAR’s Institute of
Medical Biology (IMB), Daniel
Messerschmidt,
and
William
Burkholder developed a method
to determine the “on” or “off”
status of genes in single cells5.
Based on Fluidigm technology,
their methodological advance
allows them to follow the DNA
methylation status in as many
as six loci simultaneously. They
showed that different epigenetic
marks generate chimeric mice with
unpredictable phenotypes, often
leading to developmental arrest.
The technique that Messerschmidt and colleagues have
developed has much potential in fertility treatment as
well as in diagnostic applications.
Highlighted papers:
1. Li, P., Yang, X., Wasser, M., Cai, Y. and Chia, W.
(1997). Inscuteable and Staufen mediate asymmetric
localisation and segregation of Prospero RNA during
Drosophila neuroblast cell divisions. Cell 90, 437-447.
2. Foronda, D., Weng, R., Verma, P., Chen, Y. and
Cohen, S. (2014) Coordination of insulin and Notch
pathway activities by microRNA miR-305 mediates
adaptive homeostasis in the intestinal stem cells of
the Drosophila gut. Genes Dev. 28(21), 2421-2431.
3. Srinivas, B., Woo, J., Leong, W. and Roy, S. (2007).
A conserved molecular pathway mediates myoblast
fusion in insects and vertebrates. Nat. Genet. 39(6),
781-786.
4. Chia, N., Chan, Y., Feng, B., Lu, X., Orlov, Y.,
Moreau, D., Kumar, P., Yang, L., Jiang, J., Lau, M.,
Huss, M., Soh, B., Kraus, P., Li, P., Lufkin, T., Lim, B.,
Clarke, N., Bard, F. and Ng, H. (2010). A genomewide RNAi screen reveals determinants of human
embryonic stem cell identity. Nature 468(7321), 316320.
5. Lorthongpanich, C., Cheow, L., Balu, S., Quake, S.,
Knowles, B., Burkholder, W., Solter, D. and
Messerschmidt, D. (2013). Single-cell DNAmethylation analysis reveals epigenetic chimerism in
preimplantation embryos. Science 341(6150), 11101112.
44
45
Genomics: Where do
we come from?
C
omparative genomics is a powerful strategy
for understanding the structure, function
and evolution of the human genome.
IMCB scientists are pioneers in the field of
comparative genomics. Established in 1991, the IMCB
comparative genomics group has been sequencing and
analyzing “model” vertebrate genomes
that have helped to illuminate genomic
features that are conserved in human and
other vertebrates, and differences that
have contributed to the unique features of
humans.
Fugu: a compact genome
In 1993, IMCB scientists showed that
although the genome of fugu, the toxic
Japanese pufferfish (Takifugu rubripes),
is only one-eighth the size of the human
genome, it contains a similar repertoire
of genes to humans, and proposed it as a
model for annotating the human genome1. This study
ushered in the era of comparative genomics and led to
the sequencing of the whole genome of fugu.
In a trailblazing study published in 19972, IMCB
scientists generated transgenic rats carrying 40 kb
of fugu genomic DNA and showed that a fugu gene
located in this fragment was expressed precisely in
the same neurons as the rat counterpart. This finding
demonstrated that the basic mechanisms of gene
regulation are largely conserved between fishes and
mammals, and paved the way for using fishes to predict
and experimentally verify cis-regulatory elements in the
human genome.
In 2002, an international consortium jointly led
by IMCB and the US Department of Energy’s Joint
Genome Institute sequenced the whole genome of
fugu3. The fugu genome was the second vertebrate
genome to be sequenced, the first being the human
genome. Comparison of fugu and human genomes
has helped identify many novel human genes and
thousands of conserved cis-regulatory elements in the
human genome.
and rare genetic diseases. Using next generation
sequencing platform, they are sequencing whole
exomes of individuals with rare genetic diseases and
their unaffected family members to identify causative
variants that could lead to novel therapeutic targets.
Elephant shark: the slowest-evolving genome
Cartilaginous fishes (the shark-family) are the oldest
group of living jawed vertebrates. IMCB scientists
Cover from Science, Vol 297, Aparicio S et al., Whole-genome shotgun
assembly and analysis of the genome of Fugu rubripes. Reprinted with
permission from AAAS. Image: April Vollmer.
Byrappa Venkatesh holding an elephant shark (Callorhinchus milii)
identified elephant shark (Callorhinchus milii) as having
the smallest genome among cartilaginous fishes and
proposed it as a model cartilaginous fish genome. In
a 2006 Science publication4, IMCB scientists showed
that the elephant shark and human share almost
twice the number of potential cis-regulatory elements
compared to teleost fishes and human, underscoring
the importance of elephant sharks as a valuable model
genome for better understanding the human genome.
Riding on these discoveries, IMCB scientists were
successful in obtaining funding from the National
Institutes of Health (NIH), USA for sequencing the
whole genome of the elephant shark. In 2014, an
international consortium led by IMCB sequenced the
whole genome of the elephant shark, the first sharkfamily member to be sequenced.5 Analysis of the
elephant shark genome demonstrated that it is the
slowest-evolving vertebrate genome, and highlighted
a family of genes crucial for bone formation in human
that underlie bone-related diseases such osteoporosis.
The study also provided novel insights into the origin of
the adaptive immune system in humans.
Other genomes
In recent years, IMCB scientists have initiated a
genome project for the Japanese lamprey (Lethenteron
japonicum), a model jawless vertebrate that represents
the oldest group of vertebrates6. IMCB scientists are
also involved in several international genome projects
such as the coelacanth (“a living fossil”), cichlid fishes,
mudskippers, seahorse and arowana genome projects.
Much of the work done on comparative genomics at
IMCB is spearheaded by Byrappa Venkatesh and Sydney
Brenner. For their work on the fugu genome, they were
honored with Singapore’s National Science Award in
2004. Venkatesh is a chairperson of “Genome 10K”,
an international project that aims to catalogue the
genomes of 10,000 vertebrates.
As IMCB strengthens its focus on translational research,
its researchers are working with clinicians to identify
causative variants associated with metabolic diseases
Pseudo-colour representation of DNA sequencing gel. Image: Ah Keng Chew.
Highlighted papers:
1. Brenner, S., Elgar, G., Sandford, R., Macrae, A.,
Venkatesh, B. and Aparicio, S. (1993).
Characterization of the pufferfish (Fugu) genome as a
compact model vertebrate genome. Nature 366, 263268.
2. Venkatesh, B., Si-Hoe, S., Murphy, D. and
Brenner, S. (1997). Transgenic rats reveal functional
conservation of regulatory controls between the Fugu
isotocin and rat oxytocin genes. Proc. Natl. Acad. Sci.
USA 94, 12462-12466.
3. Aparicio, S., Chapman, J., Stupka, E., Putnam, N.,
Chia, J., Dehal, P., Christoffels, A., et al. (2002).
Whole-genome shotgun assembly and analysis of the
genome of Fugu rubripes. Science 297, 1301-1310.
4. Venkatesh, B., Kirkness, E., Loh, Y., Halpern, A.,
Lee, A., Johnson, J., Dandona, N., et al. (2006).
Ancient noncoding elements conserved in the human
genome. Science 314, 1892.
5. Venkatesh, B., Lee, A., Ravi, V., Maurya, A., Lian,
M., Swann, J., Ohta, Y., et al. (2014). Elephant shark
genome provides unique insights into gnathostome
evolution. Nature 505, 174-179.
6. Mehta, T.K., Ravi, V., Yamasaki, S., Lee, A.P., Lian,
M.M., Tay, B., Tohari, S., Yanai, S., Tay, A., Brenner,
S. and Venkatesh, B. (2013) Evidence for at least six
Hox clusters in the Japanese lamprey (Lethenteron
japonicum). Proc. Natl. Acad. Sci. USA. 110: 1604416049.
46
Structural Biology:
Form begets function
S
tructural biology allows scientists to unravel
the molecular mechanisms or chemistry that
underlies all biology. For example one can
“look” at the atomic structure of proteins
bound to DNA, RNA, or small molecules in order to
understand how proteins carry out their functions.
These atomic structures provide the basis for many
important discoveries in molecular biology, and what
goes wrong in disease. Further, by looking at pathogen
proteins and how they attack their hosts, we can design
better drugs.
Controlling DNA replication
The genomes of eukaryotes are much larger than those
of bacteria. This demands a faster rate of DNA replication
during the S phase of the cell cycle. Each chromosome
is replicated only once per cell cycle. Geminin and its
associating partner CDT1 ensure a tight control of this
single replication event. IMCB scientists determined the
structure of the business core of geminin and proposed
a mechanism of its interaction with CDT11.
Controlling protein translation
Programmed cell death protein 4 (Pdcd4), a novel
tumor suppressor protein, inhibits translation through
interaction with translation initiator eIF4A, resulting
in the suppression of neoplastic transformation and
tumor invasion. The structure of Pdcd4 in complex
with eIF4A solved in IMCB revealed the mechanism by
which Pdcd4 exerted its inhibitory effect on translation
initiation2.
Putting the brakes on cell growth
The Hippo signalling pathway controls organ size and
deregulation of this pathway often occurs in human
cancers. Signals that activate the Hippo pathway
change cell transcription through the protein YAP,
whose biological function is mediated by the TEAD
Neurospora crassa (a filamentous fungus) is a single
celled organism, which forms larger communities
via cell-cell contacts, which are connected by a pore.
Material can flow from one cell to another cell through
the pore. To regulate this process, Nature has provided
a plug made predominantly from a single protein Hex1,
called the Woronin body (named after the discoverer).
The structure of Hex1 was solved by Swaminathan’s
group at IMCB, which unraveled the mechanism of
Woronin body assembly5.
Good and bad polymers
Robert Robinson’s group specializes in understanding
how protein polymers are organized. They have
demonstrated that a human mutation in the calciumbinding site of gelsolin leads to conformational
instability and subsequent cleavage to form a peptide
fragment, which self assembles to form amyloid fibrils
in the disease familial amyloidosis Finnish type6.
Movement in cells is often powered by polymerizing
proteins that can form filaments. It is the way in which
actin filaments are capped and uncapped that allows
the cell to control how much force is generated for cell
movement and in processes such as metastasis7.
Highlighted papers:
1. Saxena, S., Yuan, P., Dhar, S., Senga, T., Takeda, D.,
Robinson, H., Kornbluth, S., Swaminathan, K. and
Dutta, A. (2004). A dimerized coiled-coil domain and
an adjoining part of geminin interact with two sites on
Cdt1 for replication inhibition. Mol. Cell 15(2), 245-258.
2. Loh, P., Yang, H., Walsh, M., Wang, Q., Wang, X.,
Cheng, Z., Liu, D. and Song, H. (2009). Structural
basis for translational inhibition by the tumour
suppressor Pdcd4. EMBO J. 28, 274-285.
3. Chen, L., Chan, S., Zhang, X., Walsh, M., Lim, C.,
Hong, W. and Song, H. (2010). Structural basis of
YAP recognition by TEAD4 in the hippo pathway.
Genes Dev. 24, 290-300.
4. Hong, X., Nguyen, H., Chen, Q., Zhang, R., Hagman,
Z., Zoorhoeve P. and Cohen, S. (2014). Opposing
activities of the Ras and Hippo pathways converge on
regulation of YAP protein turnover. EMBO J. 33(21),
2447-1457.
5. Yuan, P., Jedd, G., Kumaran, D., Swaminathan, S.,
Shio, H., Hewitt, D., Chua, N. and Swaminathan,
K. (2003) A HEX-1 crystal lattice required for Woronin
body function in Neurospora crassa. Nature Structural
Biology 10, 264-270
6. Nag, S., Ma, Q., Wang, H., Chumnarnsilpa, S., Lee,
W. L., Larsson, M., Kannan, B., HernandezValladares, M., Burtnick, L., and Robinson, R. (2009)
Ca2+ binding by domain 2 plays a critical role in the
activation and stabilization of gelsolin. PNAS 106,
13719-13724.
7. Hernandez-Valladares, M., Kim, T., Kannan,
B., Tung, A., Aguda, A., Larsson M., Cooper, J. and
Robinson, R. (2010). Structural characterization of a
capping protein interaction motif defines a family of
actin filament regulators. Nat. Struct. Mol. Biol. 17(4),
497-503.
Oncogenic protein YAP interacts with TEAD through its 1 and 2 helices and
the PXX P motif.
family of transcription factors. The structure of the
YAP-TEAD complex3 solved by Haiwei Song’s team
revealed the molecular basis of YAP/TEAD interaction
and has offered a new strategy for cancer therapeutics
by targeting their interaction.
A pre-replicative complex (pre-RC) forms to initiate bi-directional DNA
synthesis during S-phase. Geminin (whose business center is a coiled coil,
shown in the center), inhibits the assembly of the pre-RC.
Recently another group of IMCB researchers found that
YAP plays an important role in tumour progression as
the intersection between tumourigenic Ras signaling
and tumour suppressing Hippo signalling4.
47
Uncapping an actin filament. The uncapping motif of CARMIL (yellow) removes capping protein (blue/red) from an actin filament (pale colours).
48
Cell & Molecular Biology:
Understanding the
building blocks of life
expression is seen in 80% of human gastric cancers.
When researchers reintroduced Runx3 into cell lines
where it had been silenced, the ability of these cells
to make tumours in mice was dramatically inhibited.
Thus restoring Runx3 expression using reagents such as
HDAC inhibitors is one option to control gastric cancer.
S
ince its inception, IMCB has contributed
significantly to research in molecular and cell
biology, publishing highly cited papers in top
flight journals in fields ranging from protein
trafficking to human health and diseases.
Pioneering methods
Most human papillomavirus (HPV) infections are
asymptomatic, but certain HPV infections drive cervical
cancer. Whether or not HPV infection develops into
cervical cancer is dependent on the type of HPV virus.
Out of the over 200 known papillomaviruses, HPV
types 16 and 18 account for 70 percent of the cases
and are deemed “high risk” infections. Typical clinical
serotyping methods of identifying HPV strains were
ineffective but in 19941, researchers led by Hans-Ulrich
Bernard published a PCR-based method to determine
HPV subtypes. Since then their method has become a
standard in HPV diagnostics, and indeed PCR methods
are used today to identify most virus infections.
Top image: The cis- (red) and trans-Golgi (green) as labelled by GM130 and
the small GTPase Arl1
Bottom image: Immune response elicited by 4 cytotoxic T cells attacking a
single P815 target cell with live labelling by tubulin tracker
Images: Lishen Loo and Wanjin Hong
Protein trafficking
IMCB has an international reputation in the field of
protein trafficking with Wanjin Hong’s group making
a great many impactful discoveries regarding SNARE
proteins. The name derives from SNAP (Soluble NSF
Attachment Protein) REceptor, and as such the SNARE
proteins comprise a protein family that helps regulate
the process of vesicle fusion.
Hong’s group has identified and functionally
characterised about half of the 38 known mammalian
SNARE proteins. For example in 1996, they published
their discovery of a Golgi SNARE (GS28) in Science2
at the same time that Nobel laureate James Rothman
described similar findings in the Journal of Cell Biology.
The lab also identified several targeting motifs for
Golgi membrane proteins and established the recycling
pathway for human KDEL receptor. Another significant
49
Mature hippocampal neuron in culture 20 days in vitro (green) co-labeled
with post-synaptic density marker PSD-95(red) to determine the spine density.
Image: Lishen Loo and Wanjin Hong
discovery has been that Arl1 GTPase regulates Golgi
targeting via the GRIP domain Golgin.
Finally a 2001 publication in Nature Cell Biology3 was
the first to uncover that the Phox domain in protiens is
designed to take proteins to membranes that contain
the phospholipid phosphatidylinositol-3-phosphate.
Development and its connection to cancer
The RUNX proteins are transcription factors found in all
multicellular animals and are responsible for processes
needed for proper development of embryos. Using
mice deficient in Runx3, researchers led by Yoshiaki
Ito showed that Runx3 is essential for normal brain
development4. They discovered that mice lacking
Runx3 had severe problems with motor coordination
in particular.
In addition to these neural defects, Runx3-deficient
mice showed a state similar to that observed during
the development of gastric cancer in humans. Ito’s
group traced this hyperplasia to an impairment of TGFβ-mediated apoptosis, suggesting that Runx3 normally
acts to suppress tumours. Remarkably the loss of Runx3
Highlighted papers:
1. Bernard, H., Chan, S., Manos, M., Ong, C., Villa, L.,
Delius, H., Peyton, C., Bauer, H. and Wheeler, C.
(1994). Identification and assessment of known and
novel human papillomaviruses by polymerase chain
reaction amplification, restriction fragment length
polymorphisms, nucleotide sequence, and phylogenetic
algorithms. J. Infect. Dis. 170(5), 1077-1085.
2. Subramaniam, V., Peter, F., Philp, R., Wong, S. and
Hong, W. (1996). GS28, a 28-kilodalton Golgi SNARE
that participates in ER-Golgi Transport. Science
272(5265), 1161-1163.
3. Xu, Y., Hortsman, H., Seet, L., Wong, S. and Hong,
W. (2001). SNX3 regulates endosomal function through
its PX-domain-mediated interaction with PtdIns(3)P. Nat.
Cell Biol. 3, 658-666.
4. Inoue, K., Ozaki, S., Shiga, T., Ito, K., Masuda, T.,
Okado, N., Iseda, T., Kawaguchi, S., Ogawa, M.,
Bae, S., Yamashita, N., Itohara, S., Kudo, N. and
Ito, Y. (2002). Runx3 controls the axonal projection of
proprioceptive dorsal root ganglion neurons. Nat.
Neurosci. 5, 946-954.
5. Li, Q., Ito, K., Sakakura, C., Fukamachi, H., Inoue,
K., Chi, X., Lee, K., Nomura, S., Lee, C., Han, S.,
Kim, H., Kim, W., Yamamoto, H., Yamashita, N.,
Yano, T., Ikeda, T., Itohara, S., Inazawa, J., Abe,
T., Hagiwara, A., Yamagishi, H., Ooe, A., Kaneda,
A., Sugimura, T., Ushijima, T., Bae, S. and Ito, Y.
(2002). Causal relationship between the loss of RUNX3
expression and gastric cancer. Cell 109(1), 113-124.
50
Cell Signalling: Sending
the right message?
C
urrent estimates suggest each human cell
contains more than 10,000 different proteins
which have to be controlled and managed
according the requirements of the tissue
in which they reside. Information from hundreds of
proteins, peptides or chemical signals present outside
the cell need to be accurately transmitted from the cell
surface to the interior where changes are made. The
code of cell signalling is far more complex for us to
decipher than the genetic code.
Phosphorylation: a common molecular switch
To understand the importance of phosphorylation one
must go back to the 1950s when Edmond Fischer and
Edwin Krebs discovered that protein kinases which
can add phosphate to intracellular proteins profoundly
change their enzyme activity. For that they were awarded
the 1992 Nobel Prize in Physiology or Medicine. IMCB
researchers were among the first to demonstrate the
widespread importance of phosphorylation comparing
the effect of TNF and IL-1, two extracellular cytokines1.
Pioneering experiments by IMCB Director Chris Tan used
high resolution two dimensional gel electrophoresis to
monitor over 450 different proteins simultaneously1.
At that time other researchers were looking at the
process of one phosphorylation event at a time. The
team found very few differences between TNF and IL-1
stimulated phosphorylation, thus suggesting that the
similar effects of TNF and IL-1 were due to overlapping
activation of the same protein kinases. It would not be
an exaggeration to say that every process in the cell is
now known to be regulated by protein phosphorylation.
Ras and Rho: keeping cells and tissues in shape
Although phosphorylation is the common currency
of signal transduction, one early puzzle was how a
small protein called Ras which only binds GTP (but is
not a kinase) could also initiate these phosphorylation
events. Mutant Ras is found in around 30% of cancers
and the oncogenic activity of Ras continues to throw
The dynamic cell cytoskeleton requires an
acto-myosin network, here marked by ArgBP2
Image: Vikas and Ed Manser
up surprises. For example Steve Cohen’s group
showed recently that mutant Ras(V12) works in part
by counteracting the “Hippo signalling” kinase casade2
- a pathway to restrict the size of our organs. Such
mutant Ras proteins are stuck ‘on’ when cells become
cancerous, and over-ride signals to stop dividing.
There are more than a hundred Ras-like G-proteins that
behave as “molecular switches” each turning on and
off their own signalling pathways. The Ras homology
proteins (Rho) were found to coordinate complex cell
sub-structures. The Glaxo-IMCB group formed by Louis
Lim spent many years tracking down the role of one
Rho member called Cdc42, and found it responsible
for formation of filopodia—finger-like extensions that
mammalian cells use to feel their environment3. It is
remarkable that a complicated organelle such as the
filopodium can be turned on by a single switch. This
ground-breaking finding provided an explanation for
the initiation of filopodia production in all human cells
including neurons.
PAK and other Protein kinases
In the early 1990s, when many of the Rho G-proteins were
discovered, the race was on to identify proteins which
were acting “downstream”. In a series of classic papers,
Ed Manser and Glaxo-IMCB colleagues demonstrated
how small G-proteins like Cdc42 could control a protein
kinase they called p21-activated kinases or PAKs4. They
also discovered that a completely different kinase ACK5
51
Institute of Molecular and Cell Biolo
Institute of Molecular and Cell Biology IMCB
Institute of Molecular INSTITUTE
and Cell Biology
OF MOLECULAR
AND CELL BIOLOGY
nonetheless shared an amino acid sequence which
allows them both to bind to Cdc42. This paved the
way for other researchers to find similar “effectors”
simply by looking at protein sequences. The PAKs play
leading roles in promoting changes to cell shape; and
one important protein that binds PAK is the fragile-X
syndrome protein FMRP6. Drugs which inhibit PAKs
have recently been shown to be effective in reversing
the changes associated with fragile-X syndrome
and schizophrenia in mice. Many pharmaceutical
companies have started to pursue PAK inhibitors as
new drug leads.
“
Our discovery of PAK was an
accident – we were not looking for these
protein kinases. Purifying PAK from the
brain then took us about two years
– Ed Manser
”
Other families of important protein kinases that were
first discovered in Singapore are ROCK7 and MRCK8.
Thomas Leung’s group has been focusing on these
effectors of Rho proteins, and demonstrated that they
are critical regulators of acto-myosin contractility and
cell movement8. Drugs which act on these two kinases
are effective in putting the breaks on migrating cancer
cells, or promoting the regeneration of nerves.
Highlighted papers:
1. Guy, G., Chua, S., Wong, N., Ng, S. and Tan, Y.
(1991). Interleukin 1 and tumour necrosis factor activate
common multiple protein kinases in human fibroblasts.
J. Biol. Chem. 266 14343-14352.
2. Hong X., Nguyen H.T., Chen Q., Zhang R., Hagman
Z., Voorhoeve P.M., Cohen S.M. (2014). Opposing
activities of the Ras and Hippo pathways converge on
regulation of YAP protein turnover. EMBO J. 33: 2447-57.
3. Kozma R., Ahmed, S., Best, A. and Lim, L. (1995).
The Ras-related protein Cdc42Hs and bradykinin
promote formation of peripheral actin microspikes and
filopodia in Swiss 3T3 fibroblasts. Mol. Cell Biol. 15,
1942-1952.
4. Manser, E., Leung, T., Salihuddin, H., Zhao, Z. and
Lim, L. (1994). A brain serine/threonine protein kinase
activated by Cdc42 and Rac1. Nature 367(6458), 40-46.
5. Manser, E., Leung, T., Salihuddin, H., Tan, L. and
Lim, L. (1993). A non-receptor tyrosine kinase that
inhibits the GTPase activity of p21cdc42. Nature 363
(6427) 364-367.
6. Say E., Tay H.G., Zhao Z.S., Baskaran Y., Li R., Lim L.,
Manser E. (2010) A functional requirement for PAK1
binding to the KH(2) domain of the fragile X proteinrelated FXR1. Mol Cell. 38: 236-49.
7. Leung T., Chen X.Q., Manser E., Lim L. (1996) The
p160 RhoA-binding kinase ROK alpha is a member of
a kinase family and is involved in the reorganization of
the cytoskeleton. Mol Cell Biol. 16:5313-27.
8. Tan I., Yong J., Dong J.M., Lim L., Leung T. (2008) A
tripartite complex containing MRCK modulates lamellar
actomyosin retrograde flow. Cell 135 (1): 123-36.
52
New Technologies:
Bringing it first
to Singapore
class facility, headed by Sudipto Roy, is accredited by
the Association for Assessment and Accreditation of
Laboratory Animal Care International. Here, a wide
range of zebrafish strains are bred and maintained
for IMCB researchers as well as other researchers at
Biopolis, in addition to services such as import and
export of zebrafish strains, fish sperm cryopreservation
and in vitro fertilisation.
Because of its fast reproductive cycle and the
transparency of its embryos, the Zebrafish is a
powerful animal model for the study of development
and physiology in vertebrates. For example, the Roy
lab discovered Foxj1 as the master regulator of motile
cilia development2, subcellular organelles that perform
important respiratory and reproductive functions in fish
and humans.
Zebrafish is also ideal to study neuronal physiology.
In a collaborative effort, the Jesuthasan and ClaridgeChang labs discovered a function of an evolutionary
ancient brain structure, the habenula, which controls
how animals may respond to the outside world. In their
study the habenula was found to control whether the
fish is attracted or repulsed by the smell of other fishes
and that this depends on the intensity of the smell3.
N
ew technologies and methodologies often
drive scientific discoveries and open the
door to new questions. Over the years,
IMCB has been instrumental in bringing new
technologies into Singapore. It has set up cutting-edge
infrastructure and technology platforms, which by and
large are available to the biomedical community.
Histopathology facility
The GLP certified AMPL located in IMCB, is a joint
effort between IMCB and Singapore Health Services
(SingHealth) headed by Soo Yong Tan. It is a onestop facility for pharmaceutical and biotechnology
companies who engage in exploratory, preclinical and
early clinical studies throughout Singapore and the
region.
Animal research services include GLP-grade animal
necropsy, histology services, immunohistochemistry,
in situ hybridisation, image analysis and veterinary
pathology evaluation. Translational services include
therapeutic target validation and drug safety evaluation.
The AMPL is also closely linked to the SingHealth Tissue
Repository, the largest human tissue research biobank
in Singapore, allowing it to generate high quality tissue
bio resources. Work at the AMPL has helped IMCB
researchers tease out the genes involved in liver cancer1.
Zebrafish facility
IMCB is home to the largest zebrafish facility in Asia,
covering an area of approximately 400 square meters
with state-of-the-art aquaculture facilities. The world-
In another project, the Tom Carney lab has looked at a
zebrafish mutation equivalent to a human bristle bone
disease4. Zebrafish embryos with such genetic defects
can be used to rapidly screen for useful drugs, a unique
opportunity that has attracted attention from partner
pharmaceutical companies.
Vladimir Korzh leads the Zebrafish Translational Unit,
taking advantage of the power of this in vivo test
system to test novel drug delivery platforms, screen for
drugs, and confirm their bioavailability.
53
Whole-genome RNAi screening facility
In 2007, IMCB set up the first whole-genome RNAi
screening facility in Singapore. Whole genome RNAi
screening is a powerful new technology used to
genetically dissect biological systems and identify novel
key players in biological pathways at the genomic scale.
The platform technology has been used at IMCB to
study how trafficking regulation at the Golgi complex
affects glycosylation in health and disease, and how
intracellular trafficking is exploited by pathogens and
toxins. The RNAi screening facility was also instrumental
in a genome-wide study of embryonic stem cells, the
first of its kind in the world5. The comprehensive screen
identified two key regulators, paving the way for future
studies in regenerative medicine.
Quantitative Proteomics
IMCB Quantitative Proteomics Group, led by Jayantha
Gunaratne plays an essential role in the current refocus
of research from Genomics to Proteomics (the study
of each protein in the cell or tissue). Using state-ofthe-art mass spectrometers, it is now possible to
quantify proteins at the femtogram level and compare
protein levels across six orders of magnitude. This
technology allows a completely different approach
to small molecule drug target-identification, and
by probing clinical samples, now affords disease
biomarker discovery. The group is well-equipped with
high resolution instrumentation, and the computing
power for rapid data analysis pipelines. A number of
MS techniques are currently only available at IMCB,
but are accessible to the community through active
collaborations.
54
55
National Science and Technology Medal
1993 : Chris Tan
Mouse Models of Human Cancer
Patient-derived human tumor tissue xenografts serve
as a powerful investigational platform to identify
and evaluate clinically directed hypotheses and could
potentially reduce animal studies. Unlike conventional
cell-line derived xenografts, these xenografts are
established directly from patient samples without in
vitro manipulation, thereby providing more accurate
depiction of human tumor biologic characteristics.
IMCB is collaborating with several hospitals in Singapore
and has established several well characterized models,
including ovarian, head-and-neck, colon and DLBCL
cancers, for industry collaborations and academic
research.
SERI-IMCB Programme in Retinal
Angiogenic Diseases (SIPRAD)
Retinal Angiogenic Diseases (RAD), such as Age-related
Macular Degeneration (AMD), diabetic retinopathy
(DR) and diabetic macular edema (DME) represent
the leading causes of vision impairment in developed
countries. SIPRAD has been established to develop
an industry standard platform in retinal angiogenic
diseases that leverages the Singapore Eye Research
Institute (SERI)’s & IMCB’s complementary expertise in
clinical and preclinical science to identify and validate
novel biomarkers and targets and evaluate potential
anti-angiogenic therapeutics in partnership with the
pharmaceutical industry
Highlighted papers:
1. Bard-Chapeau, E., Nguyen, A., Rust, A., Sayadi, A.,
Lee, P., Chua, B., New, L., de Jong, J., Ward, J.,
Chin, C., Chew, V., Toh, H., Abastado, J., Benoukraf,
T., Soong, R., Bard, F., Dupuy, A., Johnson, R.,
Radda, G., Chan, E., Wessels, L., Adams, D., Jenkins,
N. and Copeland, N. (2014). Transposon mutagenesis
identifies genes driving hepatocellular carcinoma in a
chronic hepatitis B mouse model. Nat. Gen. 46, 24-32.
National Science Award/President’s Science Award:
1995 : Catherine Pallen
1996 : Kam Man Hui
1999 : Wanjin Hong
2001 : Xiaohang Yang
2001 : William Chia
2004 : Byrappa Venkatesh
2004 : Alan Porter
2005 : Lianhui Zhang
2007 : Uttam Surana
2010 : Yoshiaki Ito
2012 : Yue Wang
Young Scientist Award
2002 : Peter Lobie
2014 : Melissa J Fullwood
Next Generation Translational Proteomics for Biomedical Discovery.
Image: Asfa Shaik, Claire Swa & Jayantha Gunaratne
2. Yu, X., Ng, C., Habacher, H. and Roy, S. (2008).
Foxj1 transcription factors are master regulators of the
motile ciliogenic program. Nat. Gen. 40, 1445-1453.
3. Krishnan S., Mathuru A.S., Kibat C. Rahman M.
Lupton C.E. Stewart J. Claridge-Chang A. Yen S.C.
and Jesuthasan S. (2014) The Right Dorsal Habenula
Limits Attraction to an Odor in Zebrafish. Current
Biology 24 (11), 1167–1175.
4. Asharani, P., Keupp, K., Semler, O., Wang, W., Li,
Y., Thiele, H., Yigit, G., Pohl, E., Becker, J.,
Frommolt, P., Sonntag, C., Almüller, J.,
Zimmermann, K., Greenspan, D., Akarsu N.,
Netzer, C., Schönau, E., Wirth, R., Hammerschmidt,
M., Nürnberg, P., Wollnik B. and Carney, T. (2012).
Attenuated BMP1 function compromises osteogenesis
leading to bone fragility in humans and zebrafish. Am.
J. Hum. Genet. 90(4), 661-674.
5. Chia, N., Chan, Y., Feng, B., Lu, X., Orlov, Y.,
Moreau, D., Kumar, P., Yang, L., Jiang, J., Lau, M.,
Huss, M., Soh, B., Kraus, P., Li, P., Lufkin, T., Lim, B.,
Clarke, N., Bard, F. and Ng, H. (2010). A genomewide RNAi screen reveals determinants of human
embryonic stem cell identity. Nature 468(7321), 316-320.
Nikkei Award
2000 : IMCB
Public Service Administration Medal
2001 : Y H Tan (Gold)
2014 : Wanjin Hong (Silver)
Public Service Administration Medal (Bronze)
2003 : Hong Lan Tay-Png
National Day’s Award
2003 : President's Certificate of Commendation for combating and
containing SARS
Nobel Prize for Medicine or Physiology
2002 : Sydney Brenner
Tomizo Yoshida Prize
2003 : Yoshiaki Ito
Buchanan Medal
2004 : David Lane
Elected as Honorary Fellow of the Royal College of Physicians
2007 : Philip W Ingham
Elected to the United States National Academy of Sciences
2009 : Neal Copeland
2009 : Nancy Jenkins
Core infrastructure and
capabilities at IMCB include:
1. Quantitative proteomics
2. Humanised mice
3. Mouse models of
human cancer
4. Protein crystallography X-ray
5. Zebrafish for drug
metabolism & toxicology
6. Advanced molecular
histopathology
7. Imaging & electron
microscopy
8. DNA sequencing
9. Medicinal chemistry &
drug development
10. Genome-wide RNAi screens
11. Monoclonal antibody
56
Continuing Scientific
Excellence: Hot off the press
D
uring the transition into an integrated
research institute focusing on human
disease pathways, translational potential
and industry interest in line with A*STAR’s
mission, IMCB scientists continue to deliver high quality
publications in top journals. Listed below are some of
the top publications from IMCB scientists in journals
with high impact factor from 2013-2015
14
Genes & Development 20
14
Genes & Development 20
57
58
Genes & Development
2014
59
60
Journal of Clinical Investigation 201
4
A Look to
the Future
1. Our up and coming PIs
2. Training the next generation
3. Alumni contributions
4. Partnering industry
Sections across an E13.5 mouse embryonic brain and stained with bIII-tubulin (green) and DAPI (blue)
Image: Shuhui Lim and Philipp Kaldis
62
63
Our up and coming PIs
I
MCB strives to maintain its record of scientific
excellence in the biomedical sciences. A new
generation of young scientists is being groomed to
maintain IMCB’s leading position and ensure talent
renewal.
Stem cells from a
drop of blood
Jonathan Yuin-Han Loh
What if you could obtain
stem cells from a simple
blood draw? As Jonathan
Loh has shown, terminally
differentiated human blood
cells can be reprogrammed
to form induced pluripotent
stem cells (iPSCs). Quick and painless for patients,
his research is an important first step towards the
application of iPSCs in the clinic.
In 2003, Loh received an A*STAR Graduate Scholarship
to carry out his PhD studies at GIS. After completing his
studies, he started working on blood-derived iPSCs at
Children’s Hospital Boston, Harvard Medical School, on
an A*STAR International Fellowship.
In 2011, Loh was awarded the A*STAR Investigatorship
Award to start his own lab, first at IMB (in 2011) and
then at IMCB (in 2012). He is concurrently an Adjunct
Assistant Professor at the NUS Department of Biological
Sciences. Accolades include the Singapore Young
Scientist Award (2009), the Singapore Youth Award
(2010) and the MIT TR35 regional award (Asia Pacific)
(2012).
A*STAR Investigatorship
IMCB is proud to be home to two
Principal Investigators who received the
prestigious A*STAR Investigatorship (A*I),
launched in 2006 to attract the most
promising young researchers from around
the world to carry out independent
research at A*STAR.
Everything is fated…
if you are a cell
Nicolas Plachta
The decisions made by
individual cells are critical
for
any
multicellular
organism. By applying
single-cell imaging in living
mouse embryos, Nicolas
Plachta is studying the
dynamic processes controlling the earliest stages of life
and problems compromising fertility.
Plachta has provided the first biophysical explanation
of how transcription factors control pluripotency—a
feature that allows cells in the embryo to differentiate
into any cell type in the body. He has also shown how
cells use a new class of filopodia to form tissue-like
structures during embryogenesis.
Formerly a Principal Investigator at EMBL Australia
since 2011 and based at Monash University, Plachta
received the 2015 A*STAR Investigatorship Award to
begin independent research at IMCB.
At the heart of genomics
Christine Cheung
Heart disease, the number
one cause of disability
and mortality worldwide,
is primarily caused by
atherosclerosis, a condition
where arteries in our
bodies become covered
with plaques, leading to
hardening and narrowing of the vessels.
To study the genetic basis of heart disease, Christine
Cheung has derived vascular smooth muscle from
patient-derived iPSC samples. She then reproduced a
spectrum of atherogenic phenotypes, with which she
hopes to identify disease biomarkers using genomewide sequencing and cell-based assays.
In 2012, Christine Cheung received a PhD degree from
the University of Cambridge under an A*STAR BS-PhD
National Science Scholarship. She joined IMCB as an IJI
in 2013.
IMCB Junior Investigator (IJI)
Programme
In 2011, IMCB launched the IMCB Junior
Investigator (IJI) programme to recruit
exceptional young scientists who have
the drive and ability to pursue their
own research programme. To date, six
excellent researchers have been recruited.
Each IJI is given a three-year contract,
with the possibility of renewal for
another three years and promotion to
a PI position. Each IJI is supported with
research funding and lab space, and
access to all shared equipment and
facilities at IMCB.
The protein
factory inspector
Huili Guo
All proteins in our body
are
made
by
large
cellular machines called
ribosomes, in a process
called translation. In recent
years, there has been
evidence indicating that the composition of ribosomal
proteins can vary and that this in turn leads to distinct
phenotypes.
Huili Guo uses a sophisticated ribosome profiling
technique that provides a codon-by-codon resolution
of the mRNA locations of ribosomes at work.
Previously, Guo used ribosome profiling to study
microRNA-mediated repression in mammalian systems,
a work that was published in Nature in 2010, and
recommended by the Faculty of 1000.
Guo received a PhD degree from MIT on an A*STAR
BS-PhD National Science Scholarship. In 2012, she was
awarded an IMCB Junior Investigatorship to conduct
independent research at IMCB. She is an adjunct
Assistant Professor at the NUS and the Lee Kong Chian
School of Medicine. In 2014, she won the L’OrealUNESCO For Women in Science Fellowship.
64
How the embryo
resets itself
Daniel Messerschmidt
During
embryonic
development,
nuclear
reprogramming
resets
the epigenome of both
parental pronuclei to a
ground state, involving
global DNA demethylation. This process, however,
poses a danger to a subset of methylated sequences
that must be inherited.
Daniel Messerschmidt, an expert in developmental
epigenetics and disease, has identified the key players
that ensure this reprogramming takes place safely. It
turns out that a key complex involving Trim28/KAP1
protects certain imprinted genes from demethylation
during reprogramming. Published in the prestigious
journal Science, his work on the maternal functions of
Trim28 and imprinting is recommended by the Faculty
of 1000.
After completing his PhD at the Max Planck Institute for
Immunobiology in Freiburg, Germany, Messerschmidt
joined the laboratory of Barbara Knowles and Davor
Solter at IMB in 2009. In 2013, he was awarded an IJI
position, followed by the prestigious National Research
Fellowship (NRF) one year later. He is also the recipient
of a 2015 NMRC Bedside to Bench Research Grant.
In 2014, Messerschmidt received the
prestigious National Research Fellowship
(NRF), which supports outstanding, earlystage career researchers in carrying out
independent research in Singapore at an
institute of their choice. Each NRF fellow
is provided with a research grant over five
years. Six calls have been launched since
May 2007, and to date, 63 NRF fellows,
representing 22 nationalities, have
received the award.
Stopping jumping genes
in their tracks
Chengqi Lin
Leukaemia—the
cancer
of the blood cells—is
a complex and multifactorial
disease.
At
the chromosome level,
translocations
involving
the mixed lineage leukaemia (MLL) gene are found
frequently in both de novo and secondary leukaemias,
leading to poor clinical outcomes.
To stop leukaemia in its tracks, Chengqi Lin has identified
the super elongation complex (SEC), which consists of
elongation factors that instruct the expression of the
MLL chimera and also the myc oncogene. Unravelling
the role of SEC further, Lin discovered that SEC also plays
a role in the productive elongation and transcriptional
activation in embryonic stem cells. His work on SEC is
recommended by the Faculty of 1000.
Lin obtained his PhD degree from the Stowers Institute
for Medical Research in 2013. He joined IMCB as an IJI
in 2013.
65
Less invasive liquid
biopsies
Huilin Shao
The growing emphasis
on personalised medicine
means that platforms that
can be used to analyse
key
biomarkers
are
urgently needed. Huilin
Shao uses nanotechnology to study biomarkers in the
bloodstream, such as from circulating tumour cells.
Unlike tissue biopsies, these “liquid biopsies” can be
obtained very conveniently and repeatedly.
In particular, exosomes – abundant membrane-bound
phospholipid vesicles (50-200 nm) actively shed off
by cells – have recently emerged as a new class of
biomarker for clinical diagnostics. Shao is investigating
the potential of using these circulating vesicles as novel
surrogate markers for clinical diagnostics.
Huilin Shao received her PhD from Harvard University,
on an A*STAR BS-PhD National Science Scholarship,
before carrying out a post-doctoral fellowship at
Massachusetts General Hospital, Harvard Medical
School. Her work has been published in top journals
such as Nature Biotechnology and Nature Medicine,
and was highlighted by the Faculty of 1000. In 2014,
Shao joined IMCB as an IJI.
Turning on the insulin
taps of our body
Adrian Teo
Early
mechanisms
underlying
human
pancreatic β cell failure
during the development
of diabetes remain unclear.
To better understand the
disease, Adrian Teo has developed a human model for
diabetes, using human pluripotent stem cells (hPSCs)
that are differentiated into functionally mature β cells.
In addition to in vitro modelling of the critical steps in
the pathway, these cells also have applications in the
clinic. Teo hopes to produce sufficient mature functional
human β cells for cell replacement therapy – patients
who receive the insulin-producing cells may regain
physiological control of their blood glucose levels.
Adrian Teo received his PhD from the University of
Cambridge on an A*STAR Graduate Scholarship
(Overseas). After post-doctoral fellowships at the IMB
and Joslin Diabetes Centre, Harvard Medical School, he
joined IMCB as an IJI in 2014. He is also an adjunct
Assistant Professor at the Nanyang Technological
University, Singapore.
66
67
Training the
next generation
O
ver three decades, many of IMCB’s former
students and postdoctoral fellows have
taken up key positions in academia,
industry and education, with others even
setting up their own biomedical companies.
PhD programme
IMCB offers an integrated graduate
programme of advanced course work,
laboratory research and seminars. To
date, IMCB’s PhD programme has
nurtured and trained more than 260
PhD students. In its current format, the
IMCB-A*GA-NUS PhD Programme in
Biomedical Sciences is the main source
of graduate student intake for IMCB.
The programme consists of four years of
study and research under the supervision
of IMCB Principal Investigators and NUS
Professors, and leads to a PhD degree
awarded by NUS.
“
”
During that time, the idea of
setting up IMCB was proposed and
accepted by the Singapore government
and active recruitment of graduate
students was underway. I was in the first
batch of PhD students recruited by Louis
Lim.
– Tuck Wah Soong
A pioneer among pioneers
Tuck Wah Soong
Among IMCB’s pioneering graduate students is Tuck
Wah Soong, Head of the Department of Physiology
at the Yong Loo Lin School of Medicine, NUS. Soong
was among the first batch of graduate students to be
recruited at IMCB, where he was supervised by Kam
Man Hui.
Following a post-doctoral stint at the University of
British Columbia, Canada, he spent three years at
IMCB as a Research Associate in Yue Wang’s group
till 1999. He then became a Principal Investigator at
the newly-established National Neuroscience Institute,
before joining NUS in 2004. He was Assistant Dean
from 2006-2008, and Head of Department since
2008, where he continues to pay it forward through
numerous education and outreach initiatives.
Advertising campaigne for the IMCB Biomedical Science Graduate Programme - Cultivate
Your Mind. Image: Ernesto Guccione
Fighting cancer is his
calling in life
Kanaga Sabapathy
Also in the lab of Kam Man
Hui, Kanaga Sabapathy
began his PhD studies in
1990, where he isolated
and characterised a unique
population of immune
cells that could recognise cancer cells lacking MHC
class I antigens and launch an immune response. He
completed his PhD studies in 1994.
Kanaga Sabapathy is now a Principal Investigator
at the National Cancer Centre Singapore (NCCS),
heading the Molecular Carcinogenesis laboratory. He
is the Chairman of the NCCS Research Committee,
where other IMCB Joint PIs such as Kam Man Hui,
Bin Tean Teh and Huynh The Hung also hold principal
appointments. In addition, Kanaga Sabapathy is also
affiliated to the Cancer & Stem Cell Biology Program
at Duke-NUS Graduate Medical School, and an adjunct
Professor at the Department of Biochemistry at NUS.
“
My days in IMCB were truly
exhilarating, as I was exposed to real
competitive science, that not only
generated the urge to succeed at
the highest level, but gave a sense of
confidence that we could do the best and
compete with the best.
”
“
At Nestlé, I have started
developing partnerships with various
A*STAR institutions since 2008.
On a personal note, I am proud
that my knowledge and passion in
molecular biology is beginning to be
valuable, thanks to the emergence of
nutrigenomics and epigenetics.
”
The science of food
Allan Lim
Allan Lim, Group Manager of Food Science & Innovation
Partnerships at Nestlé Singapore, joined IMCB in 1989.
Under the tutelage of Benjamin Li, he carried out a PhD
project where he characterised a human DNA repair
enzyme. Upon graduating in 1995, he decided that his
calling was in applied research and joined the Nestlé
R&D Centre in Singapore as a chemist.
Wanting a change in scenery, Lim joined Kemin
Industries in 2004 as Research Manager, acting R&D
Director and Senior Scientist, where he managed the
development of enzymes, toxin binders, probiotics
and emulsifiers for the animal feed industry in the Asia
Pacific region. He returned to Nestlé in 2008 for a new
role in promoting innovation partnerships in the AsiaPacific region.
68
Even undergraduate
students get a chance
Huck Hui Ng
Never a dull day at IMCB
Bor Luen Tang
Starting first as a Junior Research Fellow in 1989,
Bor Luen Tang of the Department of Biochemistry
at the NUS obtained his PhD degree in 1994 under
the supervision of Wanjin Hong. Calling it a “vibrant
metropolitan melting pot” of experiences, Tang
remembers the “very generous financial backing in
the institute” and “fantastic in- house administrative,
logistic and centralised facility support” while he was
there.
After continuing his research as a post-doctoral fellow
in Hong’s lab, he started a tenure- track position at IMCB
and NUS in 2001. To help nurture the next generation
of scientists, Tang is currently Deputy Executive Director
of the NUS Graduate School for Integrative Sciences
and Engineering (NGS).
“
My formative years spent in IMCB
were a wonderful experience…One could
not help but learn by osmosis. I picked up
all the cell biology I needed from Wanjin
and others in the lab, but over the years
also had some knowledge of Drosophila
and yeast genetics infused in me by the
neighbours.
”
Few may know this, but
Huck Hui Ng, the Executive
Director of the GIS, started
out his research career at
IMCB under the supervision
of Benjamin Li studying the
DNA repair mechanism in cells.
“
As an undergraduate, I did not
have many opportunities to interact with
the senior scientists. However, I did get
to know a number of inspiring scientists,
including Tom Leung, Bill Chia, Uttam
Surana and Pua Eng Chong, along the
research journey. When they talked about
science, you could see the glow in their
eyes and feel their conviction for science
and their subjects.
”
Research Fellows
IMCB has to date recruited more
than 800 PhDs from the international
community. These high-flying researchers
come from all over the world and are
recruited for their strong scientific track
record and desire to contribute to high
impact research in Singapore.
From signal regulation to regulatory affairs
Jennifer Cairns
Jennifer Cairns, Director of Regulatory Affairs at Sanofi
US, was a post-doctoral Research Fellow at IMCB from
1990-1993. She worked on TNF signal transduction
with Graeme Guy, whom she had met while she was
working at the University of Birmingham in the UK. She
remembers the camaraderie within the group, and the
friendships forged during her three-year stint at IMCB.
In 1997, Cairns joined French pharma Rhone Poulenc
Rorer at their UK site. Two decades later, she still works
at the same company, although the company name
has now changed. In her new role in Sanofi US, she
interfaces with the FDA in Washington on behalf of the
company for various projects.
“
My first impression of IMCB
was this very imposing prestigious glass
building perched on top of a hill. The
IMCB laboratories offered “state of the
art” equipment and technology that
I had not seen before in my previous
life in academia in the UK. When I look
back, I’d like to think that my affiliation
with IMCB did have an impact on my
successful move into the industry.
”
69
“
IMCB seemed to be a perfect
match for both my scientific interest and
my desire to work a while abroad. Uli’s
enthusiasm about his research lab and
also about everything else Singapore
had to offer made my decision easy. I
was planning to stay for three years but
it became close to eight years, and I
enjoyed every moment of my stay.
”
She came for three
years, stayed for eight
Doris Apt
Doris Apt, Senior Clinical
Science
Specialist
of
Oncology at Genentech
Inc. in San Francisco, joined
IMCB after completing her
PhD at the German Cancer
Research Centre (DKFZ). At IMCB, she worked with.
Hans-Ulrich Bernard on the human papilloma virus
(HPV).
Apt witnessed Singapore’s reputation as centre of
research excellence grow over the years. At her first
Keystone meeting for Transcription, no one had heard
of Singapore and her work was treated with scepticism.
A few years later, she received a much warmer response.
Apt joined Maxygen in 1997 and moved to clinical
research at Genentech Inc. after 13 years. She remains
a regular visitor to Singapore, attending Genentech’s
South-East Asian Investigator Meetings and visiting its
clinical sites located here.
70
“
The early days at IMCB were
not easy as the lab had to be set up
– ordering of chemicals, glassware,
equipment etc. besides the pressure
to publish. Nonetheless, it was a lot of
fun with labmates, especially Shanthi
(Shanthi Wasser, Head of Scientific and
Business Management at IMCB). I guess,
as pioneers, we were expected to achieve
a lot within a very short period of time, to
bring IMCB to the world stage. The best
thing for me was, once you have survived
IMCB, you can excel anywhere! IMCB has
indeed armed me well.
”
The ‘plant people’
Mee Len Chye
Mee Len Chye, the Wilson
and Amelia Wong Professor
in Plant Biotechnology at
the University of Hong
Kong, was a Research
Fellow at IMCB from 19871993. She worked in the
Plant Molecular Biology Laboratory under Nam Hai
Chua, after answering a recruitment advertisement
when she was studying for her PhD at the University
of Melbourne.
At IMCB, she studied isoprenoid biosynthesis in the
rubber tree, Hevea brasiliensis, and worked specifically
on 3-hydroxy-3-methyl-CoA reductase, an enzyme in
the isoprenoid pathway. Chye fondly recalls her group
of plant biologists at IMCB, who referred to themselves
as the “plant people”.
71
IMCB years gave him a
confidence boost
Paramjeet Singh
Paramjeet Singh, Vice
President and Head of
Research and Development
at Cerebos Pacific Limited,
was
a
Postdoctoral
Researcher at IMCB from
1991-2010, after completing his PhD in Biochemistry
at NUS.
Wanting to more directly contribute to society, Singh
singled out research on dietary bioactives for its
potential to affect many lives. He joined Cerebos Pacific
Limited in 2010, a research-based health supplements
enterprise operating across the Asia-Pacific region. He
began as Chief Scientist, and is now also Vice President
and Head of Research and Development.
“
I found the transition [to industry]
to be quite easy as my experience at
IMCB helped me develop a yearning
for scientific independence and the
confidence to take up completely
new areas of research. For this, I am
particularly thankful to Wanjin Hong who
allowed me free rein to take up a diverse
set of research projects.
”
A coronal section across an E13.5 mouse embryonic brain and stained with antibodies against
Musashi (red) and DAPI (blue). Image: Shuhui Lim and Philipp Kaldis
72
73
Alumni
contributions
W
here IMCB is today is due to the
foundational work of extremely
talented alumni. Most telling of its
success throughout the years, 14 IMCB
Principal Investigators have received National Science
and Technology Awards and Medals. Collectively, these
alumni have helped IMCB publish more than 2,000
publications, many in top international journals. They
are now leaders in academia and industry, holding
key positions in pharmaceutical, biotech, medical
technology and nutrition companies, both in Singapore
and farther afield.
The IMCB experiment
Hans-Ulrich Bernard
Hans-Ulrich Bernard, who is currently a Professor
at University of California, Irvine, was a Principal
Investigator at IMCB from 1987-2002. He recalls
receiving a call from Louis Lim at the German Cancer
Research Centre in Heidelberg, where he was based, in
response to an application he had sent to IMCB.
published a stream of high impact publications about
HPV transcription and evolution. Today, he remembers
his 15 years at IMCB as “professionally the most
valuable time of my career”.
“
The years have passed. Thousands
of excellent publications have emerged
from IMCB. Most of the staff at IMCB 25
years ago are now in leading positions
throughout Singapore as well as in
multinational companies, which became
attracted to invest in Singapore by IMCB’s
well- trained manpower. The experiment
is a success.
”
After accepting the interview and receiving an offer,
Bernard joined about ten freshly hired Principal
Investigators at IMCB, who were tasked to establish a
state-of-the-art molecular biomedical research institute
in Southeast Asia, in what he dubbed the “IMCB
experiment”. Over the years, Bernard and his team
“
Someone called Louis Lim,
unknown to me at that time, was on
the line: ‘You seem to know a lot about
sexually transmitted diseases, we need
someone like you in Singapore’.
”
Structure of gelsolin. Image: Robert Robinson
‘Spinning off’
BTI from IMCB
Kong Peng Lam
Kong Peng Lam, Executive
Director of Bioprocessing
Technology Institute (BTI),
was a Principal Investigator
at IMCB from 1998-2005,
after
a
post-doctoral
fellowship at the University of Cologne in Germany.
Lam’s group was the first to generate gene knockout
mice in Singapore. He recalls his amusement learning
that he had to have “armed escort” while transporting
gene knockout mice from the airport to IMCB in the
middle of the night.
Lam became an important player in the transition
to Biopolis, overseeing IMCB’s relocation as Deputy
Executive Director of the BMRC, and later as its
Executive Director. He returned to full-time research
as Founding Executive Director of the Singapore
Immunology Network (SIgN) in 2006, later joining BTI
in 2008, helmed by Miranda Yap, where he has been
Executive Director since 2011. Accolades include EMBO
and HFSP Fellowships, NUS Outstanding Researcher
Award, Singapore Youth Award (S&T) and the Arthur
Kornberg Memorial Award.
“
In a way, I have come full-circle.
BTI was once partially housed in IMCB
and Miranda Yap’s office was on the
second floor in the “Blue Fish Tank on
the Hill”. Today, BTI and IMCB enjoy an
excellent relationship and collaborate
extensively on research projects.
”
“
[A*STAR] invited us to set up a
lab and offered to give us everything we
needed. We’ve been travelling our whole
lives and Asia is our favourite place to
visit. We thought, if we’re going to have
an adventure, why not Singapore? We
can live somewhere we love and help to
build something, rather than stay in the
US, where everything seemed stagnant.
So we went there in 2006.
”
A synergy of
the best minds
Neal Copeland and
Nancy Jenkins
Neal Copeland served
as Executive Director of
IMCB from 2007-2010.
For more than 30 years, he
has worked together with
Nancy Jenkins to model human disease in the mouse,
with a focus on cancer. Together, they are among the
50 most cited biomedical Research Scientists in the
world today.
During his time as Executive Director, Copeland
streamlined operations at IMCB and implemented
individual group research operating budgets. Over a
five-year period, the pair modelled 16 different human
cancers in mice using a transposon system they had
developed. In 2009, Neal Copeland and Nancy Jenkins
were elected to the US National Academy of Sciences.
They are now based at the Methodist Hospital Research
Institute in Texas as Senior Members.
74
A*STAR’s Chief Scientist
David Lane
David Lane has served in key
strategic roles at A*STAR
for more than a decade. He
was the Executive Director
of IMCB from 2004-2007,
and during his tenure, he
recruited
internationally
famous scientists and set up the ETC to advance and
accelerate drug development in Singapore.
Lane discovered the p53 tumour suppressor protein
during his post-doctoral studies, which he dubbed
the ‘guardian of the genome’. He has won many
international prizes and awards in addition to a
knighthood in 2000 for his contribution to cancer
research.
In 2012, David Lane was appointed Chairman of
Chugai Pharmabody Research Pte Ltd, which he
serves concurrently as Chief Scientist of A*STAR, and
Executive Director of the p53 Laboratory, A*STAR.
“
It excites me to see the pace
science is developing and how IMCB,
myself and my colleagues can have the
privilege to be part of the life science
revolution that is going to be the key to
the 21st century.
”
75
How cells respond to stress
Shengcai Lin
China’s scientific
heavyweight
Zhihong Xu
Zhihong Xu was Vicepresident of the Chinese
Academy of Sciences (1992
– 2003) and President of
Peking University in China
(1999-2008) before retiring
in 2008. A plant biologist by training, Xu has served
in senior scientific management positions in China. He
did a sabbatical at the Chua Lab in IMCB in the late
1980s and continued to visit IMCB when he served on
Temasek Lifescience Laboratories’ Scientific Advisory
Board.
A love for zebrafish
developmental biology
Jinrong Peng
Jinrong Peng was a
Principal Investigator at
IMCB from 2002-2008,
following the merger of
IMA with IMCB. His studies
have focused on zebrafish
developmental biology, with newer research on the
role of p53 and Def-interacting factors for digestive
organ development in zebrafish. He is now a Professor
at Zhejiang University in China.
Shengcai Lin was a Principal Investigator at IMCB from
1995-2001, before joining the Hong Kong University
of Science and Technology as an Assistant Professor
from 2001-2006. He is currently Dean of the School
of Life Sciences at Xiamen University in China, and his
research broadly covers metabolic homeostasis and the
control of cell growth.
A RUNX switch in cancer
Yoshiaki Ito
Yoshiaki Ito was a Research
Director at IMCB from
2002-2008. He is best
known for his discovery of
the RUNX family of genes,
which are involved in the
development
and
the
pathogenesis of cancer. He became Deputy Director of
the Cancer Science Institute of Singapore (CSI) from
2008-2012, and is now Professor of Medical Oncology
at the Yong Loo Lin School of Medicine, NUS. Ito
received the 2010 President’s Science Award for his
discovery of the role RUNX3 plays in gastric and colon
cancers while he was based at IMCB and CSI.
Other notable alumni in academia include:
William Chen
(NTU)
Eyleen Goh
(Duke-NUS)
Kah Leong Lim
(National Neuroscience
Institute)
Kam Man Hui
(NCCS)
76
77
Partnering
industry
Other notable alumni in academia include:
Catherine Pallen
(University of British
Columbia, Canada)
Peng Li
(Tsinghua University,
China)
Notable alumni in industry:
Emilie
Bard-Chapeau
(Novartis Institute of
Biomedical Research,
Switzerland)
Calvin Boon
(Life Technologies
Singapore)
I
MCB was launched in 1985 as the keystone for
development of biomedical R&D capabilities in
Singapore. Its early success led to the concept of
Biopolis as an academic-industrial complex, allowing
easy access between basic science and downstream
players. Through its strategic focus on important areas
of basic research, IMCB seeks to remain relevant within
the evolving biomedical landscape.
In addition to its legacy role, IMCB forms an important
arm devoted to A*STAR’s mission. BMRC has diversified
its industry engagements to include med-tech, food
and nutrition and personal care. IMCB will continue
to focus on linking to pharm-bio, with targeted
collaborations in other industry sectors. It is notable
that two of A*STAR’s research institutes – the BTI and
ETC – have their origins within IMCB.
Even in the early days, IMCB was looking to industrial
interactions and forging collaborations with multinational companies such as Glaxo Wellcome (now
GSK). Basic research begun at IMCB has often been
commercialised through licensing of its intellectual
property portfolio.
Across Singapore IMCB is strategically integrated with
the larger biomedical research community. The PIs have
joint faculty positions, run joint labs and have research
collaborations with NUS, NTU, SingHealth and DukeNUS Graduate Medical School. Internationally, IMCB’s
collaborations have grown and diversified, a selection
of which are covered in the following pages.
With a tradition of scientific excellence based on PIdriven research, IMCB is meeting the challenges of the
future by focusing on human disease pathways, and by
linking these with discovery research with translational
potential. IMCB typically provides the scientific
underpinning required by the industry partners to
develop products for the market.
David Murphy
(University of Bristol, UK)
Nathan Subramaniam
(Queensland Institute
of Medical Research,
Australia)
Rosemary Tan
(Veredus Labs)
Thuan D Bui
(i-DNA Biotechnology)
Ong Siew Hwa
(Acumen Research Labs)
Ceremony marking Glaxo-IMCB collaboration: Sir Paul Girolami (left) and Chris Tan (right).
78
79
Industrial partnership
highlights
VISION
The original vision of IMCB
was to foster a vibrant research
culture to enable cutting edge
discoveries and nurture highquality talent. Today, her vision
is to remain a premier cell and
molecular biology institute with
increasing focus on addressing
the mechanistic basis of human
diseases.
MISSION
Our mission is to:
1. conduct cutting-edge
discovery research in disease
pathways
2. groom early career
researchers to be future
leaders in their fields
3. collaborate with medical &
industry communities
for research impact
IMCB's research is grouped under two major research
areas: Discovery research and Translational research.
Discovery research:
1.
2.
3.
4.
Animal Models of Development & Disease
Cancer & Stem Cell Genetics & Genomics
Structural Biology & Drug Discovery
Cell Biology in Health and Disease
Translational research
1.
2.
3.
Humanized Model Organisms for
Human Diseases
Systems Approach for Disease Target
Identification & Validation
Protein Engineering & Antibody Development
for Diagnostics & Therapeutics
1989-1995
I
MCB’s earliest R&D partnership was signed with
GlaxoWellcome in 1989. The $50 million tie-up
provided blue-sky funding for 15 years towards
an IMCB research programme under Louis Lim
to investigating the mechanisms at play in neurodegeneration. The partnership was a prelude to a
commercial joint venture in 1993 between Glaxo and
EDB, called the CNPR. Miranda Yap headed CNPR
from 1993 until 2000, a unit devoted to screening
for novel bioactive compounds derived from plants,
micro-organisms and marine organisms. IMCB also
worked with Glaxo Group Research to sequence the
Helicobacter as the initiating agent of gastric cancers.
IMCB pioneered transgenic rat technology and was
contracted by Amylin Corporation to provide genetically
engineered rats to model human type II diabetes. The
October 1991 issue of FORTUNE magazine highlighted
the Institute in its race to commercialise transgenic rat
technology by Qi Zeng, then working in David Murphy’s
and David Carter’s lab.
Seeing an opportunity for IMCB to benefit from
relationships with large multinational biotech
companies, IMCB and EDB founded Singapore BioInnovations Pte Ltd which acquired 4.2% of Amylin
Corporation and 1% of Gilead Corporation.
In these early days IMCB also had a reputation for
expertise in orchid hybridisation and cloning. In 1995
NSTB provided funding for a $4.5 million joint venture
with orchid grower Wiltech Agro.
Strategic R&D partnerships in the 1990s
included the world-wide distribution
of TNF-β by Genzyme and Boehringer
Mannheim. IMCB also spun-off
Singapore’s first life-science venture,
GeneSing, to manufacture a new betainterferon called Glycoferon™, a madein-Singapore therapeutic for the AsiaPacific market.
80
1996-2005
R
elationships with Canadian collaborators
deepened with an IMCB start-up Terragen
Inc. formed with MDS, the largest healthcare
venture company in Canada. In 1998, the
Institute entered into an agreement with the Medical
Research Council of Canada and Vancouver’s Centre
for Molecular Medicine & Therapeutics for a new R&D
partnership in genetic medicine.
From 1993-2000, Yue Wang built up a microbial
collection containing ~10,000 actinomycetes strains
isolated from tropical rainforests in Singapore.
Publication of this actinomycetes collection attracted
interest from Roche Pharmaceuticals, which signed
a three-year agreement with IMCB from 1996-1998
to integrate the collection into its drug screening
programme. In 1998, Roche signed a supply agreement
deal to obtain these natural product extracts.
The economically crippling 2003 SARS
outbreak in Singapore, led to a bringing
together of research resources across
the island. IMCB researchers Yee Joo
Tan and Masafumi Inoue developed two
ELISA tests with Genelabs Diagnostic Pte.
Ltd. to diagnose SARS from just a drop
of serum, plasma or blood. As a result
IMCB received the National Day’s Award
(President’s Certificate of Commendation)
for combating and containing SARS).
The CNPR was spun-off from IMCB in 2002 as MerLion
Pharmaceuticals Pte Ltd. which acquired all of CNPR’s
assets, including the actinomycetes collection and
a portfolio of promising lead compounds. MerLion
nonetheless remained a key partner for IMCB in its
various drug discovery activities.
2005-2010
2011-2015
W
A
ith malaria still the scourge of
Southeast
Asia,
a
DNA-based
diagnostic test for for early and rapid
confirmation of malaria infection was
jointly developed by Robert Ting (IMCB) and the NUS
researcher Ursula Kara, and commercially launched in
2005 by Veredus Laboratories Pte Ltd. Thousands of
patients have since benefitted in India, Pakistan, Laos,
Singapore and Indonesia.
Understanding the legacy of our genome to disease
susceptibility includes understanding the epigenetic
regulation of human genes. IMCB and Hitachi Software
Engineering Co. Ltd., Japan jointly developed a new
method of detecting DNA methylation to assist in the
early detection and diagnosis of cancer. In 2006, IMCB
licensed its DNA methylation assessment technology to
Hitachi Asia Ltd. for use in research and hospital labs.
A joint venture aimed at the identification of novel
enzymatic drug targets for oncology was initiated
between Eli Lilly and Ernesto Guccione of IMCB in
2009. The Eli Lilly researchers have moved back to
Indianapolis but this remains an active and thriving
research collaboration.
s IMCB has moved its discovery research
in human disease pathways towards
translational research, the engagements
with industry partners have blossomed.
In 2014 alone, 14 new projects were initiated with
industry partners.
Human skin research has attracted significant recent
investment in Singapore. Multi-lab IMCB partnerships
are ongoing with Procter & Gamble (P&G), with Walter
Hunziker and Ernesto Guccione working with Bob
Isfort and Tom Dawson of P&G on programmes in hair
quality and skin barrier function. Separately Fred Bard
has carried out large-scale RNAi screens to understand
how skin constituents are regulated, while John
Connolly works with P&G on hair follicle-associated
immune cells and their contribution to hair health.
Wound repair remains huge healthcare burden. A
diabetic skin model developed by Andrew Tan is being
used by Johnson & Johnson (J&J). Better mice models
also mean more accurate drug screening. Qingfeng
Chen is partnering with John Luk at J&J using mice
DEVICES. Frederic Bard began a
collaboration with Namyong Kim of
Curiox Biosystems Pte Ltd. The four-year
partnership has led to the development
of wall-less plates, called Droparray™,
that are now sold worldwide.
ChipSeq tracks. Image: Diana Low and Ernesto Guccione.
81
Bill Burkholder and Steven Quake of
Stanford University are collaborating
with Fluidigm to develop ultra-sensitive
biochemical assays using microfluidic
devices.
Monoclonal Antibody. Image: Edward Manser.
with human hepatocytes that are susceptible to
the hepatitis B virus. Similarly Chen has a different
humanised mouse which Merck & Co are using to test
new immuno-modulatory therapies.
A pipeline of monoclonal antibodies covering
therapeutic and diagnostic applications have come from
IMCB’s Monoclonal Antibody Unit (MAU) previously
headed by Le Ann Hwang and now by Yee Joo Tan. In
2014, four monoclonal antibodies developed at IMCB
were licensed to Singapore Advanced Biologics (SABio)
for commercialisation.
Induced pluripotent stem-cell (iPSC) research promises
to revolutionize stem cell therapies. Jonathan Loh has
worked with Singapore-based Cordlife Limited since
2014 to develop chemically-induced iPS cells and ‘best
practice’ protocols using banked cord blood.
Any commemorative publication would not be
complete without a nod to history. An investment
made in 1993 has recently paid off handsomely: the
IMCB spin-off MerLion Pharmaceuticals successfully
carried out Phase II clinical trials in 2014 for urinary
tract infection using Finafloxacin, which was then
approved in February 2015 by the FDA. Finafloxacin
has also been approved by the FDA for the treatment
of “swimmer’s ear”, acute otitis externa.
82
83
JOINT PIs
With Singapore-MIT Alliance for Research and Technology (SMART)
With National University of Singapore
Biochemistry
Department
Cancer Science Institute
and Yale-NUS College
Duke-NUS Graduate
Medical School
Qingfeng Chen
Jean Paul Thiery
Adam ClaridgeChang
Melissa J Fullwood
Mechanobiology Institute
Timothy
Saunders
Lei Sun
Microbiology Department
Marius Sudol
Justin Chu
With A*STAR RIs
Bioinformatics
Institute
of Medical
Institute:
Biology:
Singapore
Bioimaging
Consortium:
Dmitry Ivanov
Weiping Han
Yee Joo Tan
Bruno Reversade
With Nanyang Technological University, Singapore
Lee Kong Chian School of Medicine, Imperial College London – NTU Singapore
George Augustine
Tom Carney
Karen Crasta
Philip Ingham
Xiaomeng
Wang
With Singapore Eye Research Institute
Tien Yin Wong
Shyam Sunder
Chaurasia
Amutha Barathi
Veluchamy
Gemmy Cheung
School of Biological Sciences
With SingHealth
Pär Nordlund
Yonggui Gao
Andrew Nguan
Soon Tan
Soo Yong Tan
Visiting Investigators
With National Cancer Centre Singapore
Kam Man Hui
Bin Tean Teh
Kanaga Sabapathy
Huynh The Hung
Darren Wan
Teck Lim
Institute for Research on Cancer and Ageing of
Nice (IRCAN), INSERM, Nice, France
Stanford University,
USA
Dmitry Bulavin
Stephen Quake
Gavin Siew
Wei Tan
IMCB Group Leaders 2015
IMCB Staff 2015
86
IMCB SAB members with
BMRC Senior Management,
March 2015
From left to right, Benjamin Seet, Wanjin Hong, Hung Mien-Chie, Thomas Südhof, Randy Schekman, Patrick
Casey, Barry Halliwell, George Radda and Juan Bonifacino.
87
88
Acknowledgements
The production of this book is supported by the IMCB 30th Anniversary Steering Committee and the Commemorative
Publication Sub-Committee.
The Committee wishes to acknowledge the contribution of the following individuals in promoting the
publication of this book:
Chuan Poh Lim, Chairman of A*STAR
Benjamin Seet, Executive Director of BMRC
Wanjin Hong, Executive Director of IMCB
Commemorative Publication Sub-Committee
Edward Manser (Chairman)
Byrappa Venkatesh
Yue Wang
Uttam Surana
Frederic Bard
Jonathan Yuin-Han Loh
Alice Tay
Shanthi Wasser
Esther Chua
June Oh
"Special thanks must go to Shanthi Wasser and Esther Chua for tirelessly working on this project" - Ed Manser
Production
Editorial and content: Asian Scientist Publishing Pte Ltd and Edward Manser
Design: BRANDX-INQ
61 Biopolis Drive, Proteos
Singapore 138673
Fax: +65 6779 1117
Email: [email protected]
Website: http://www.imcb.a-star.edu.sg/php/main.php

CELEBRATING - Institute of Molecular and Cell Biology

Transcription

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