Issue 10 Special Feature: High Impact Papers by Malaysians
1. Prof. Sheila Nathan
Lee, SH, Wong, RR, Chin,, CY, Lim, TY, Eng, SA, Kong, C, Ijap, NA, Lau, MS, Lim, MP, Gan, YH, He, FL, Tan, MW & Nathan, S (2013). Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor. Proc Natl Acad Sci USA, 110:15067-15072.
Prof. Sheila Nathan and her group are based at Universiti Kebangsaan Malaysia (UKM).
Impact of this work to the society
Prof. Sheila Nathan (SN): Bacterial pathogens use multiple mechanisms to survive and multiply within an infected host, including diminishing the host’s ability to defend itself from pathogenic assaults. We identified a new immune suppression mechanism by Burkholderia pseudomallei, the causative agent of the human disease, melioidosis. Using the worm Caenorhabditis elegans as the infected host, we analysed the worm’s gene expression profile in response to B. pseudomallei infection. We demonstrated that B. pseudomallei recruits the host’s own degradation mechanism to specifically degrade the host GATA transcription factor. This GATA factor is critical for host immune defense, thus its degradation leads to suppression of the host’s effective antimicrobial defense.
SN: The findings presented in this publication involved over four years of experimental work and was undertaken in collaboration with Dr. Man-Wah Tan from Stanford University, USA. To conduct the experiments involving C. elegans, we established the C. elegans Research Facility in UKM, the first of its kind in Malaysia. The facility serves as a repository for wild type, mutant and reporter worm strains whilst also housing equipment for culturing worms and high-end fluorescent microscopes. The facility has also been utilised in a spin-off project to screen for molecules with anti-infective properties towards B. pseudomallei utilising the C. elegans infection model.
SN: The expression profile data featured in this article proved to be a useful resource for information on potential worm antimicrobials as well as a source of biomarkers for assessing bacterial virulence. To date, our group has identified and characterised two new potential antimicrobial peptides towards B. pseudomallei that confer both antibacterial and host immunomodulation properties. In addition, we have utilised a worm detoxification enzyme within a fluorescence reporter worm strain to identify a potential B. pseudomallei-specific toxin. The antimicrobial peptides could be an alternative therapeutic to combat melioidosis whilst the reporter worm may function as a useful screen for bacterial toxins.
2. Mamduh A. Zabidi
Zabidi, MA, Arnold, CD, Schernhuber, K, Pagani, M, Rath, M, Frank, O & Stark, A (2014). Enhancer—core-promoter specificity separates developmental and housekeeping gene regulation. Nature, 518:556-559.
Mamduh Zabidi is currently a PhD student in Stark Lab, based at Research Institute of Molecular Pathology, Vienna, Austria.
Impact of this work to the society
Mamduh Zabidi (MZ): There are thousands of genes in every genome, and they can be divided into two large classes: genes that are needed in every cell (so-called housekeeping genes), and genes that are only activated in specific cells (tightly regulated genes). So far, it has been unknown how the differential control of these gene classes is achieved.
This study shows that these two gene classes differ in the characteristics of two key DNA regulatory elements: promoters (regions upstream of genes where DNA transcription is initiated) and enhancers (stretches of the genome that carry the information about when and where a gene is to be activated). Moreover, there is mutual specificity between the two classes of promoters and enhancers and they are activated by different protein factors.
These results provide insights on how cells ensure that only appropriate genes are activated. These findings might explain certain diseases caused by gene misregulation, such as cancer.
MZ: This study is a combination of computational and laboratory bench work, which took about two years to complete. The team has been greatly supported by the excellent infrastructure, in particular the next-generation sequencing facility as well as the computational infrastructure at the Institute of Molecular Pathology (IMP) and the Vienna BioCenter (VBC).
SN: The team is currently working on several related projects to follow up on this work and extend the findings to other systems and species.
3. Peng Weng Kung
Peng, WK, Kong, TF, Ng, CS, Chen, L, Yong, H, Bhagat, AAS, Nguyen, N-T, Preiser, PR & Han, J (2014). Micromagnetic resonance relaxometry for rapid label-free malaria diagnosis. Nat. Med., 20: 1069-1073.
Weng Kung is based at BioSyM, SMART, Singapore. BioSyM.
Impact of this work to the society
Weng Kung (WK): We built an economical, benchtop magnetic resonance relaxometry (MRR) that could detect as few as ten Plasmodium parasites in a drop of blood. Plasmodium parasites are the causative agent of malaria, an infectious disease commonly found in tropical countries. By exploiting a waste product of Plasmodium that serves as a natural magnetic label for MRR detection, this benchtop system offers improved sensitivity, speed, and accurate detection of Plasmodium-infected blood. The small footprint of this system also makes it cheaper to make in comparison to traditional magnetic resonance systems. With this benchtop MRR system, it is possible to screen for malarial infection within minutes, and without the hassle of transporting blood specimen to a clinical setting.
WK: I am very fortunate to be in my current department and institute, which provide a unique opportunity to work on basic and translational research. We started this project four years ago, working closely with a team from Nanyang Technological University, who helped with the mouse model work. With a background in physics and engineering, I knew almost nothing about malaria back then, but I was very determined to contribute my expertise to the biomedical community. Overall, this multidisciplinary project was made successful by biologists and engineers.
WK: Our team is currently working on a field-deployable MRR system that is robust enough to be used by minimally trained healthcare workers to diagnose malaria. Another goal of this system is to be able to detect malarial parasites in asymptomatic patients, who have the potential to become sources of future outbreaks.
In addition to this malaria project, I am also involved in other clinical collaborations involving diabetes and endometriosis. I am looking forward to set up my own research group soon to better understand various diseases and come up with solutions for the issues surrounding them. My focus within the research group would be on the engineering aspect–setting up and fixing the “nuts and bolts” of the research, and all the way to solving/understanding diseases at a molecular level.
This article first appeared in the Scientific Malaysian Magazine Issue 10. Check out other articles in Issue 10 by downloading the PDF version for free here: Scientific Malaysian Magazine Issue 10 (PDF version)