Fighting back against ageing
In a bright, cheerful lab, Dr Sze Siu Kwan works to pinpoint exactly how the human body degenerates. His research focuses on tracing the progression of disease back to its protein foundations, which dictate cellular biological function. Spontaneous processes, chemical activity, and numerous other factors can impact protein structure, which can contribute to ageing, neurodegenerative disease, dementia, diabetes, heart disease, and the like.
Thanks to improvements in public health, nutrition, and medicine, human life expectancy has increased rapidly in recent years, but unfortunately so has the incidence of diseases that affect the elderly such as heart disease, dementia and stroke. While tackling age-related disorders now represents a major challenge throughout the modern world, there are still surprisingly few research teams focusing on these these conditions. Dr. Sze Siu Kwan's team, at the Nanyang Technical University in Singapore, aims to understand how the human heart and brain become damaged as we get older.
Ageing and degeneration
Dr. Sze explains that heart and brain tissues are made up of many different proteins which can change shape over time and become altered by chemical reactions that prevent them from performing their normal functions. His lab studies how these ‘degenerative protein modifications’ (DPMs) can eventually stop major organs from working correctly, leading to the debilitating symptoms that we recognize as heart disease and dementia.
Since individual human proteins are extremely small, and the chemical changes these undergo are even smaller still, Dr. Sze stresses that progress in this field is heavily dependent on technological advances in the laboratory. “While we wait for new tools to be developed, we have to improvise and make what we already have work more effectively.”
Innovation and new technology
In his own laboratory, Dr. Sze and colleagues recently developed a new sample separation method which he explains can be used “as a kind of metal detector”, that assists in the identification of disease-causing DPMs. This is just one of the challenges facing Dr. Sze and his team. “We have to scour very large data sets on a regular basis,” he says, pointing out that basic programming skills will greatly benefit future researchers aiming to work in this field.
Without diverse skills to draw on and ongoing technical innovations in his own lab, it would be extremely difficult to identify some of the DPMs that we now recognise as promoting disease in human patients. Key to Dr. Sze’s success has been his chemical physics background, which has helped him to develop new ways of analysing data, thus enabling his discovery of new DPMs that are now thought to play an important role in damaging brain neurons in dementia.
Degenerative protein modifications
Dr. Sze explains that while DPMs can form naturally in the human body, brain cells are normally able to reverse these changes using a critical repair protein that protects against tissue damage. But this repair protein can itself become altered by age-related DPMs that prevent it from working properly, leading to progressive tissue damage and disruption of crucial biological processes.
Since the human body is made up of a huge number of these proteins which can be modified in many different ways, it is a major challenge to understand how these initially form and subsequently interact during ageing, leading to degenerative diseases in some individuals but not others. However, unravelling these events could not only improve our understanding of several major human diseases, but also shed new light on the biology of the ageing process itself.
Dr. Sze’s recent work suggests that a lack of oxygen in the heart or brain can alter cell chemistry to promote DPM formation, leading to tissue damage and eventually impairing organ function. Dr. Sze explains that these discoveries were made possible through the use of ‘systems biology’ techniques that provide rich information on the genetic profile and entire protein content of an individual patient sample, all at the same time.
“We use all the ‘-omics’ technologies together, combining genomics and proteomics methods to probe deeper into disease processes and make important new discoveries.”
An interdisciplinary approach
Dr. Sze’s diverse background has been vital to the success of his approach. “Chemical physics is very interesting, but as a postdoc I found myself increasingly drawn to figuring out how biology works. The physical, living world is an amazing series of processes, constantly growing and changing.”
Dr. Sze’s knowledge of computer programming and expertise in mass spectrometry have been vital to his rapid progress since refocusing his research onto the role of protein biology in major human diseases. As a result, Dr. Sze credits the Croucher Foundation’s early support for allowing him to make the transition from the physical sciences to biomedicine, where he has since been able to develop a highly successful interdisciplinary research lab.
Since adopting this new direction in his research, Dr. Sze’s lab has established a number of links with leading medical institutes around the world, which give his team vital access to high-quality biobanks of patient samples, medical records, and clinical data.
By integrating these data with his innovative laboratory methods, Dr. Sze aims to identify specific protein changes in patient samples that can be used to predict clinical outcomes and perhaps even inform physicians about the best treatments options.
“Clinical samples are crucial for our studies, but tissue can be difficult to source,” says Dr. Sze. His team therefore works closely with both clinicians and university colleagues in Singapore, and has also forged strong collaborations with biobank projects and universities in several other countries including the Netherlands and Germany. By pooling resources, these biobank initiatives aim to address some of the biggest healthcare challenges facing the modern world.
Consequently, the study of human protein biology has developed rapidly in recent years, although many exciting advances have yet to be translated into effective new therapies. However, Dr. Sze remains optimistic that the future applications of his research will yield genuine improvements in healthcare for the increasing number of people around the world who suffer from severe age-related disorders. While Dr. Sze jokes that, “we’re not ready to put it into a face cream just yet!”, ongoing work in his lab may one day make this a reality.
Dr. Sze Siu Kwan was awarded a Croucher Foundation studentship while pursuing a B.Sc. in chemistry and was later awarded his doctorate in chemical physics at the University of Hong Kong. From 1995 to 2002, he was a Croucher fellow at the University of Toronto and later took up a postdoctoral post at the University of Waterloo, where his work focused on chemical physics and protein chemistry. After serving as a visiting proteomic scholar at Cornell University, he then joined the Genome Institute of Singapore in 2002, before finally moving to the School of Biological Sciences at Nanyang Technical University in 2006. Since joining NTU he has established the school’s proteomics facility and currently serves as its director.
To view Dr Sze’s personal Croucher Profile, please click here.