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  30 June 2014  
  Boon Chuan LOW  
 




Associate Professor and Principal Investigator
Cell Signaling and Developmental Biology Laboratory Department of Biological Sciences
National University of Singapore, and Mechanobiology Institute Singapore

Boon Chuan LOW, Ph.D
Research Fellow in Graeme GUY’s Lab from 1995 - 2000



Chapter 1:
Science is about “discovering truth and creating new knowledge” – charting a beginner’s path (1990-1995).

I left Kuala Lumpur, Malaysia, for Dunedin, New Zealand in the early 90’s to pursue my dream as a scientist. I believed that science would provide unlimited potential in conquering every quest for the betterment of humankind. It is not just the philosophy of finding the truth that answers our curiosity, but using our answer to create new knowledge that will bring benefits to humanity and attain progress in our society. THIS belief has never changed.

I set out on my innocent path of “truth discovery” by aiming to be a genetic engineer, a highly uncommon profession in the eyes of many of my friends and teachers, and certainly to my parents and siblings.  Fortunate to be selected to study in New Zealand, first at the King’s High School and then The University of Otago (http://biochem.otago.ac.nz), I set my goal firmly to pursue my dream undergraduate program at the Department of Biochemistry. From there, I continued to receive my postgraduate training under my first mentor Dr Murray Grigor where we figured out how the transport of glucose and amino acids occurs and is regulated in response to hormonal changes and nutrient fluxes. The names GLUT1, GLUT4, System L and System y+ that describe various transporter systems still remain vivid today and more importantly, they have become some of the major foci in understanding metabolic regulation in human physiology and pathologies.

Chapter 2:
The entrancing journey at the emergent Science Hub of Asia, Singapore (1995-2000, IMCB)

Eagerly wanting to contribute to science while receiving world-class training without being too far away from home, I landed myself in IMCB soon after my PhD. I had earlier applied for the Lee Kuan Yew Postdoctoral Fellowship with an intention to join IMCB but the application file was filed “KIV” by the HR department as I had not been officially conferred the degree yet. Surprisingly, my application dossier was spotted and brought “alive” by Dr. Graeme Guy (GG), my soon-to-be mentor who is now retired but a very active master of both photography arts as well as science (http://grguy.smugmug.com/).  A few exchanges of emails sealed my fate in IMCB and my science career thereafter. What promised to come next was an exciting and entrancing journey of growth and re-discovery of myself in science.

While travelling down my memory lane, I can’t help but to trace every part of my presence at the IMCB, from the “open air” cubicles on the top level of the building where you could literally yell down the beautifully designed “atrium”, to the quiet and solemn reading room (yes, that was the IMCB library) where one the best collections of up-to-date journals were kept. The sound of homogenizer grinding through cultured cells and rat tissues in the cold room would pierce your eardrums if you did not step out of the room unless you wore an ear protecting gear (of course, nowadays, you have to install a sound-proof enclosure to keep the homogenizer in and to conduct an SOP and risk assessment before you can operate this machine). The excitement of looking at confocal images and witnessing how my BCH domain proteins induced dynamic cell morphologies are inforgettable – even though those were fixed samples taken from the confocal microscopes, instead of the spin-disks that our students use so routinely these days. The most suspenseful wait was whether any scientific “truth” would be discovered when our X-ray films rolled in the “film developer” and came out from the other end, capturing our most important western blot results. Those moments seemed to last an eternity even though the wait was two minutes in a very dimly lit “dark room”…. As a biochemist whose discovery rested so much on western blots that reveal the mystery of protein-protein interaction network, such an experience was both an anxious and very hopeful one. “There is always the light at the end of a tunnel” as  I often quip to motivate my aspiring students.

A myriad of vivid facial expressions and voices around me, and our active corridor discussions seemed to have happened only yesterday. The camaraderie in the GG group and as well as friendships forged at IMCB (such as with Li Peng, Cheng Gee, Tuck Wah, Yoon Pin, Bor Luen, Cheh Peng, Permeen, Jeffery Tan, just to name a few) and the inspiring mentorship of Graeme Guy as well as support from other gurus like Ed Manser, Thom Leung, Xinmin, Uttam, Kong Peng, Walter, Victor Yu, Shengcai and Wanjin, helped me sail through my 5 years in IMCB relatively painlessly. The spirit of sharing and teaching, collaboration and constructive criticisms smoothened my learning journey. I was particularly blessed to have a great friend and mentor like Graeme, who would make (plenty of) room for my new venture in other areas of cell signaling and who also provided me with the opportunity to mentor the young guns in his group.  He constantly pushed for very high standards of science among us and his obsession for indisputable western blots and images were legendary. In addition, he introduced the very first series of animated “Powerpoint” presentations in IMCB and set lofty benchmarks for the rest of the institute to maintain.  His immense openness no doubt had facilitated my transition to a new life in academia.

Chapter 3:
The birth of the BCH domain and its role as a p(l)acemaker scaffold protein in cell and metabolic signaling (2001- current)

Given room to develop one’s interest in science is a huge blessing, especially with such an intense competition globally, and from the demand and expectation that are being judged primarily by the impact factors of journals nowadays. In the earlier years, we were not overly concerned about impact factors. While CNS (Cell, Nature and Science) journals were the dream journals, the likes of MCB, Oncogene and JBC and several others also received just as much attention from peers. I enjoyed my scientific exploration with sincere expectation and freedom. The first breakthrough came when I identified BNIP-2 as a novel partner of the FGF receptor tyrosine kinase through the yeast 2-hybrid screen. Confirming BNIP-2 as a substrate for this important receptor in cells had proven very elusive by means of co-immunoprecipitation studies until I engineered the kinase-dead mutants of this receptor to trap BNIP-2 in a tight complex. This would explain the lack of detection based on their “kiss and run” transient interaction. Function of BNIP-2 was completely unknown at that time, except that its C-terminus shares a highly conserved region with Cdc42GAP, an inactivator for the small GTP-binding proteins (or GTPaseses) that act as molecular switches of signaling in cell growth and cytoskeleton network. I named the region BCH (for BNIP-2 and Cdc42GAP Homology).  The years 1999 and 2000 saw my first 3 consecutive JBC papers reporting on how BCH domain mediates its interaction with itself or other similar BCH domains, and also its unexpected direct liaison with GTPases.

An opportunity then arrived so with my passion to join academia, I gladly took up the Assistant Professorship at the Department of Biological Sciences, National University of Singapore (http://www.dbs.nus.edu.sg/) and unknowingly became part of the first exciting wave in the major transformation in Life Sciences, spearheaded by the then Head, Emeritus Prof Hew Choy Leong. This significant milestone coincided with the expansion of the Biomedical Sciences Initiatives in Singapore. That was brilliant timing.

Although trained as a biochemist, I realized that the best practice in science education is not just about imparting what I know to students and getting them do what I want or do what I think is right. Instead, I want to fill in the gaps of knowledge by learning along with students who have sparks in their eyes. Soon, I started to see myself and students (undergraduates and postgraduates) embrace new platforms of molecular, cellular and developmental biology, bioimaging, functional genomics and proteomics, structural biology, bioinformatics, computational biology and more recently the realm of mechanobiology (see below). This exciting scientific endeavor would not have been possible without the unparalleled spirit of enthusiasm from my students and my fellow colleagues who have the desire and faith to learn and to collaborate together.  I was honored to receive the Singapore Young Scientist Award in 2005 for the pioneering work in discovery of the BCH domain (http://www.a-star.edu.sg/Awards-Scholarship/Young-Scientist-Awards/Past-YSA-Winners/YSA-Winners-2003/Winner-Citation-Dr-Low-Boon-Chuan.aspx). Ten years on and kudos to the my these great young minds and collaborators, we have mapped and understood better the mechanisms by which BCH domains exert their signaling impacts on cell growth, differentiation, apoptosis, morphogenesis, cell migration and tissue/organ development (link to the review article on BCH domain in special issue of FEBS letters).  

Chapter 4:
Science has its unlimited company.

The cell is considered as an autonomous machine that builds upon various highly sophisticated systems that bring every “part” alive in response to both external and internal cues.  Although we start to piece up what these essential parts are, we are still far from understanding precisely how they are integrated across molecular, cellular, tissue, organ, system, and organismal levels. More importantly, cells do physically interact with other neighboring cells as well as their immediate microenvironment defined by the myriad of extracellular matrix composition and the different mechanical forces that they experience and exert. The latter include, for examples, the compression, expansion, shear, stretching, tension and geometry. To fully understand cell function, we need to understand the biochemical and physical bases that control various biological processes so faithfully in healthy condition and to find out what, where and when some of these “parts” go wrong in disease states (link to PDF of Hippo/YAP review in FEBS Letters 2014).

Armed with these key fundamental questions and under the leadership of Profs Michael Sheetz, Paul Matsudaira and Hew Choy Leong, we started to bring together a group of scientists and engineers, all under one roof after convincing the Ministry of Education and the National Research Foundation to establish the world’s first Research Centre of Excellence in Mechanobiology in 2009. This RCE soon transforms itself into a full-fletch Mechanobiology Institute Singapore (www.mbi.nus.edu.sg). By using different concepts and tools developed in molecular and cell biology (including the state of the art bioimaging suites), physics, engineering, computational modelling, mathematics and nanoscience disciplines, we thrive to systematically unravel mechanisms that define molecular mechanics, cell mechanics and tissue mechanics. Hopefully, we would have an informative Functional and Repair Manual in Cell Functions for students, scientists, engineers and clinicians of all levels. Our peer-written MBInfo Wiki “A modular approach to cell function” is moving towards just that (http://www.mechanobio.info/).

As part of our focus to decipher mechanism of cell signaling, my research group aim to decode cell signaling in the context of mechanosensation and mechanotransduction to define how cells and tissues sense, read and transduce both mechanical and biochemical signals to make cells tick as an autonomous machine. Encouraged by our pioneering work with the BCH domain-containing family proteins, we examine how cells and tissues respond to both biochemical and physical environments by specifically modulating the activities of scaffold proteins and their immediate cellular targets (http://mbi.nus.edu.sg/low-boon-chuan/). These cellular targets include GTPases (e.g Rho, Ras, RhoGAP, RasGAP), kinases (e.g. MAPKs, Hippo), metabolic enzymes (e.g. glutaminase and ATP citrate lyase) and gene transcription regulators (e.g. YAP). We go on to emphasize the expanding roles of scaffold proteins, not as an inert passive devices, but an emergent class of versatile multi-faceted p(l)acemakers that control cell signaling at the right space and at the right time (review on scaffold protein in Cellular Signalling). To help understand how some of these key proteins function in vivo, we have developed zebrafish as the alternative models to mice, including the first in vivo model of single- and double-transgenic and inducible Rho and Ras oncogenes that drives or impedes liver cancer (http://www.straitstimes.com/the-big-story/case-you-missed-it/story/clue-slowing-liver-cancer-lies-zebrafish-20131025) . Other zebrafish models for understanding organ development and metabolic signaling are currently underway.

It has been a long time since I left IMCB. While establishing my scientific research base in NUS and MBI, I do come back to this alma mater institute from time to time to serve in advisory committees  for graduate students’ theses and to engage friends and colleagues in various aspects of research collaboration. IMCB has moved from the tranquil location at Kent Ridge hill, to the semi-metro-like Biopolis. In the early days, sightings of small cobras and monkeys were not too uncommon, while the chirping of birds and crickets was a welcoming symphony as I walked through the woods behind the building.  The old IMCB building has since been refurbished to the Life Science Institute of NUS. The open “atrium” of the building that once stood elegantly in the lobby has been “reclaimed” to make way to house more scientists. However, what is most important is the pivotal role that IMCB played in nurturing many of our contemporaries and the many more generations of scientists that follow.  I take pride in being an alumnus of the institute who witnessed her rapid growth on the world stage.

Perhaps I may be over-romanticizing my time in Singapore in this exercise in nostalgia, and perhaps it's because I spend an inordinate amount of time nowadays writing and assessing grant applications but I can truthfully say that working in IMCB was one of the most productive, enjoyable and fulfilling periods of my research career. I am extremely thankful to IMCB for the post-doc opportunity, Graeme Guy for his guidance, my GG lab 'mates' for their camaraderie and Executive Director Professor Hong Wanjin for his suggestion that I share my experience on this website.



 

 
     

 
 
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