Translating Research: From Lab to Bedside. Treating. Differently. July 2014 Vol. 18 No. 7. Translating Research at SingHealth: Cancer

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Treating Asthma 49 Differently July 2014 Vol.

Translating Research: From Lab to Bedside

Cardiometabollic Diseases 29 SingHealth: Eye

1 Treating Asthma 49 Differently July 2014 Vol. 18 No. 7 A monthly international biotechnology publication We speak to Associate Professor Lee Pyng about tips on how to deal with asthma, current asthma treatments as well as a new treatment for severe asthmatics, Bronchial Thermoplasty. Translating Research: From Lab to Bedside SingHealth: Cancer 25 SingHealth: Cardiometabollic Diseases 29 SingHealth: Eye Diseases 33 SingHealth: Health Services Research 37 SingHealth: Infectious Diseases 41 SingHealth: Neurosciences (Stroke) 45 MCI (P) 194/03/2014

EDITORIAL Translational Medicine to bridge the Valley of Death between Discovery and Clinical Application Why is it that in 2008, 800,000 medical research papers were published, but by 2011 only 21

2 EDITORIAL Translational Medicine to bridge the Valley of Death between Discovery and Clinical Application Why is it that in 2008, 800,000 medical research papers were published, but by 2011 only 21 new drugs were approved by the US Food and Drug Administration 1 barely per cent of the discoveries? Of the numerous research feats worldwide, how many can boast that they have actually made a real impact to improving patients lives? Much has been said about the chasm between laboratory discoveries and clinical care outcomes. Biomedical researchers and clinicians dub this the valley of death, where basic biomedical discoveries initially generate exciting new results, but subsequently languish, failing to translate to actual improvements for clinical medicine and healthcare. But how do we ensure that research endeavors reach and make a tangible difference to patients? Translational medicine is the bridge to this valley. Translational medicine is, essentially, the process of applying knowledge gained from basic biomedical research to clinical practice; it involves bridging new research findings, scientific discoveries and new techniques to approaches in the prevention, diagnosis or treatment of disease. This can be in the form of drugs, devices, biomarkers or treatment methods. Translational medicine involves the pursuit of the patient s health as the ultimate outcome. It involves paradigm shifts such that scientific discoveries should not just be celebrated only in basic laboratories and research institutes or published (and archived) in prestigious medical journals they need to make their way to hospitals, clinics and into patients lives to be real successes. In the US, the National Institutes of Health (NIH) recognizes the importance of translational medicine and has made it a priority. Since 2006, the NIH has formed centers of translational research at its institutes with a budget that has reached $500 million a year 2, and it has launched translational science awards for researchers. Similarly, Singapore s national biomedical sciences agenda has identified translational medicine as a priority and focus area and has placed emphasis on such research that creates greater health and economic impact. There have been successful cases to date, which is an encouraging sign. An example close to home is the management of Singapore s unique problem of high rates of childhood myopia. It is a common condition and is almost a national problem affecting 28 per cent of children as young as seven years of age, with the rate hitting 83 per cent at 18 years of age 3. Check out our website at Sign up for our mailing list to get updates at Air your views and suggestions by writing to in to the editorial team (Letters to the Editor) at biotech_edit@wspc.com 3

For 16 years, researchers and subsequently clinicians at the Singapore Eye Research Institute (SERI) and the Singapore National Eye Centre (SNEC) have been trying to tackle this problem.

The work was done with an end goal in mind to decrease the rising incidence of myopia, and to slow down the condition in its tracks.

3 For 16 years, researchers and subsequently clinicians at the Singapore Eye Research Institute (SERI) and the Singapore National Eye Centre (SNEC) have been trying to tackle this problem. 16 years is no short duration, but translational medicine requires a long-term view. The work was done with an end goal in mind to decrease the rising incidence of myopia, and to slow down the condition in its tracks. SNEC s research team discovered that eye drops with low-dose atropine slows down the progression of myopia in children with minimal side effects. After years of tests and clinical trials, the clinicians and researchers have transformed their findings into a solution. SNEC today now offers new eye drops with a 0.01 atropine dosage the most effective atropine level proven to combat myopia for children with severe myopia in a dedicated myopia clinic, and is furthering their research to meet regulatory demands. With translational medicine, this nationwide problem may become a non-issue in the foreseeable future. In this issue of Asia Pacific Biotech News, I have invited healthcare and research professionals from SingHealth to share on headway in translational medicine in pertinent research fields cancer, cardiovascular disease, health services research, infectious diseases, neurosciences, as well as eye diseases. These six fields address common diseases and biomedical priority areas in Singapore and Asia, and are also the research focus areas of the SingHealth - Duke-NUS academic medical centre in Singapore 4. What are the ingredients for successful translational medicine? First, driving translational medicine requires a new model of working together. Multidisciplinary collaboration across specialties, disciplines and industries is the key to driving translational research to success. You would notice that the contributors comprise clinician, clinician scientists, scientists, nursing and allied health professionals. For instance, an observation in the clinic by a doctor may give rise to a hypothesis that a scientist in the lab can work on. A scientist s discovery may translate into a biomarker that acts as clinical tool for the clinician, or a drug target for drug development by a pharmaceutical company. A physiotherapist s inspiration may result in the invention of a rehabilitation device that could not be made possible without collaboration with an engineering or medical technology institution. Research is not an individual event; it is a team sport with different roles and skills for each team member. Sustained collaboration can bring drugs, treatments and care outcomes out of the valley of death. Second, a strong ecosystem and culture that sustains and rewards translational medicine is critical. It involves forging a close partnership between a hospital cluster and a university, the concept of the Academic Medical Center or Academic Healthcare Cluster. The partnership must align the traditional divergent missions of healthcare and education, and the cultural differences between academic researchers and practicing doctors. Third, translational medicine requires people who understand both science and medicine clinician-scientists. The clinician-scientist can effectively act as a connector between scientists and doctors and must speak both languages. To translate research, young clinician-scientists must be identified, trained, mentored and supported. In the US and other countries, clinicianscientists face significant challenges in funding and career development5. The final piece of translational medicine is policy implementation. Once new discoveries and clinical evidence have been established, government agencies and healthcare systems should have a clear framework to implement health care policy and public health policy accordingly. The importance of policy implementation as the final step in the valley of death cannot be underestimated6. I hope that you will find inspiration from this month s issue and work towards making your research and work one that truly impacts patients lives. 4 ASIA PACIFIC BIOTECH NEWS

References 1 Bornstein, D. Helping New Drugs Out of Research s Valley of Death. The New York Times, 2008. http://opinionator.blogs.nytimes.

html 3 Prof Ian G Morgan PhD, Prof Kyoko Ohno-Matsui, Prof Seang-Mei Saw. Myopia. The Lancet, 2012. http://www.thelancet.

4 References 1 Bornstein, D. Helping New Drugs Out of Research s Valley of Death. The New York Times, Butler, D. Crossing Valley of Death. Nature, news/2008/080611/full/453840a.html 3 Prof Ian G Morgan PhD, Prof Kyoko Ohno-Matsui, Prof Seang-Mei Saw. Myopia. The Lancet, Prof Ranga Krishnan, Prof Ivy Ng. Academic Medicine: Vision to Reality. Ann Acad Med Singapore Jan;42(1): Roberts SF, Fischhoff MA, Sakowski SA, Feldman EL. Perspective: Transforming science into medicine: how clinician-scientists can build bridges across research's "valley of death". Acad Med Mar;87(3): ue=03010&article=00011&type=abstract 6 Jiang F, Zhang J, Wang X, Shen X. Important steps to improve translation from medical research to health policy. J Transl Med Feb 8;11:33. Professor Wong Tien Yin is the Group Director of Research at SingHealth and the Vice Dean of Clinical Sciences at Duke-NUS Graduate Medical School, Singapore. SingHealth and Duke-NUS is the largest academic healthcare cluster in Singapore. He is concurrently a senior ophthalmologist and Deputy Medical Director of the Singapore National Eye Centre, and ranked as the world s top eye disease researcher according to ExpertScape. He has published more than 800 articles in peer-review journals, and is the co-inventor of 10 patents. 5

FEATURE Picture credit: NIAID/Flickr/CC SingHealth: Eye Diseases Associate Professor Louis Tong Senior Consultant, Corneal and External Eye Service, Singapore National Eye Centre; Head, Ocular

5 FEATURE Picture credit: NIAID/Flickr/CC SingHealth: Eye Diseases Associate Professor Louis Tong Senior Consultant, Corneal and External Eye Service, Singapore National Eye Centre; Head, Ocular Surface Research Group and Co-head, Ocular Inflammation and Immunology Research Group, Singapore Eye Research Institute; Associate Professor, Office of Clinical, Academic and Faculty Affairs, Duke-NUS Graduate Medical School 33

6 FEATURE Introduction End stage ocular surface disease (OSD) is a major blinding condition in Asia and the world. Corneal blindness affects 6.8 million people in India, contributes to 16 per cent of blind children in Nigeria, and is responsible for eight per cent of blindness in Shanghai, China. Regardless of the cause of the initial problem, which may be severe chemical injury, severe allergic disease, autoimmune disease or infections, relentless chronic eye or ocular surface inflammation is the driver that leads to this devastating end result. In the early stages of inflammation, immune cells of various types get recruited to the eye and secrete various growth factors that increase the opacity of the cornea or the light transmitting tissue of the eye. In the later stages, fibroblasts and contractile cells called myofibroblasts may be involved that secrete scar tissue. In addition, abnormal blood vessels grow onto the cornea that rapidly becomes opacified and largely untreatable. Even surgery has poor outcomes in such scenarios. Without any doubt, the understanding of how inflammation can be controlled in OSD is key to resolving this condition. Ocular Surface Research In Asia, ocular surface research related to inflammation, is spearheaded by researchers from just two countries: Japan and Singapore. At the Singapore National Eye Centre and Singapore Eye Research Institute, a series of competitive research grants have enabled the establishment of the Ocular Surface Research Group in This group is focused on the evaluation of clinical aspects of inflammation, such as clinical trials with the latest modalities of treatment for severe dry eye, imaging of inflammation related eyelid disease and tearfilm, as well as basic molecular processes that are involved in inflammation and modulation of wounding in the ocular surface. While research in Japan has preceded that in Singapore for many years, there have been a host of significant breakthroughs in Singapore in the recent years. This is in part attributed to several key changes in Singapore; increased competitive funding on eye and interdisciplinary research, emphasis on translational clinical research, recognition of clinician-scientist careers, establishment of academic medical centers and investment in biomedical infrastructure such as the Biopolis. Dry eye Dry eye is perhaps the most common example of OSD. Because of its high prevalence, it is also a significant socioeconomic burden on patients and society. One example of a unique collaboration involving the Ocular Surface Research Group is the Collaborative Research Initiative in Meibomian Gland Dysfunction (CORIM) which involves researchers from the Singapore Lipidomics Incubator of National University of Singapore, physicists from Ngee Ann Polytechnic, imaging specialists from the bioinformatics institute of Agency for Science technological and Research (A*STAR). This four-way collaboration has not only revealed novel lipid molecules present in the human tear, but also identified lipids that are deficient in dry eye and important for tear evaporation function. Excessive tear evaporation or instability is responsible for most cases of dry eye and inflammation related to oil producing glands of the eyelid called Meibomian glands. Specific members of lipids can be increased by treatment, and this finding is promising for translation to human use. We published two original articles on this topic in January 2014 in the Journal of Lipid Research, and this research was also highlighted in the American Society of Biochemistry and Molecular Biology (ASBMB) Today webpage in February this year. 2 The ASBMB, founded in 1906 as American Society of Biological Chemists, has 12,000 members today, and is the principal forum for the dissemination of American research on the chemical aspects of biology. We are pleased to learn that the lipid composition of the tear is of interest to general biologists. Inflammation Inflammation affects the ocular surface in myriad different ways. One of the initial processes that must happen for the eye in OSD to recover is for the protective epithelial cells to adhere and migrate over diseased areas. This is one part of a complex process of wound healing. Recently in June 2013, we published a paper that documents the molecular events that underlie the adhesion and migration of these cells in the journal Biochim Biophys Acta, and identified some molecular targets that may be helpful for clinicians to use as therapeutic targets in ocular surface disease. This research has taken a few years, involving scientists from Singapore as well as from the Victor Chang Cardiac Research Institute in Sydney Australia, and involves genetically modified animals from the institute in Sydney. The publication has been highlighted in a web-based Global Medical Research abstract recently, and circulated to various stakeholders in the biomedical scene. 3 Currently our researchers have continued these efforts into mechanobiology, in a collaboration with the University of Paris in a Merlion France Singapore PhD Program. Research into the cornea and tears Research in the cornea and the tears is particularly exciting because of the accessibility of the tissue to live-imaging and instrumentation. In animal-based as well as in human experiments, it is possible to observe the migration of epithelial cells, circulating immune cells, abnormal blood vessels and exogenous therapeutic molecules tagged with a visible dye. For this reason, researchers are interested to test drugs or toxicity using an ocular surface based strategy. Our research also involves the profiling of the immune system using impression cytology techniques that allow us to longitudinally track patient s progress. The ocular surface cells can be evaluated further with techniques like polymerase chain reaction for gene expression and flow cytometry for immunotyping. Soluble mediators of inflammation are secreted into patient s tear film, which can be collected and analysed with various antibody based or mass spectrometry based techniques. We are involved in a few biotechnological collaborations 34 ASIA PACIFIC BIOTECH NEWS

7 FEATURE with engineers to evaluate tear molecules in ocular surface inflammation. Through these ways, we hope to understand how autoimmune systemic diseases like rheumatoid arthritis can increase inflammation in the ocular surface. In terms of diseases, the eye is indeed the window to the body. The setting up of the SingHealth Translational Immunology and Inflammation Centre in Singapore is a key initiative that will help such research. Conclusion How can understanding basic science help patients? In OSD, understanding of the need for vital growth factors in the tear prompts us to use autologous or patients own plasma to treat severe OSD. The living cells from the surface of the eye require nourishing proteins and other factors to keep inflammation in check. Patients from the ocular surface clinic have benefitted from a technique that processes their plasma into eyedrops for therapy 4. We are currently in discussion with Blood Services Group from the Health Science Authority to help provide this service for OSD patients. The ocular surface research group is also actively involved in commercializing research for the health care industry. For example, a partnership with Mediworks, a company in China, has allowed us to incorporate our original image analysis algorithms 5,6 in the new software that accompanies the slit lamp biomicroscopes. The hardware is an essential, basic equipment for any ophthalmic clinic or eye hospital anywhere in the world. However, a slight modification in the hardware can also allow this to document damage and changes to the oil producing glands in the eyelid. Inflammation in the eyelids destroys these glands, and the loss and alteration of morphology of the glands can be monitored non-invasively in human patients over time. We hope that through this project, a practical method that is relatively inexpensive and accessible to developing countries can be developed for assessment of inflammation in patients. One of the areas that will be most actively researched in the next decade is how inflammation in the eyelid eventually contributes to the tear and ocular surface disease. Our research in imaging and expertise in clinical trials will position us well as we sail into this exciting era. Indeed Singapore should definitely actively pursue in translational research and at the same time provide excellent related healthcare, so that it can serve as a regional and global key opinion leader in this field. References 1. Tan DTH, Beuerman RW. Ocular Surface Research at the Singapore Eye Research Institute The Ocular Surface Vol. 7, Issue 2, Pages JLR/DryEye/ 3. molecular-mechanism-transglutaminase-2-cornealepithelial-migration-adhesion/ 4. Petznick A, Tong L, Chung R, Wang JC, Koh M, Salleh R, Waduthantri S. Autologous plasma eyedrops prepared in a closed system: a treatment for dry eye. Eye (Lond) Sep;27(9):1102. doi: /eye Koh YW1, Celik T, Lee HK, Petznick A, Tong L. Detection of meibomian glands and classification of meibography images. J Biomed Opt Aug;17(8): doi: /1. JBO Celik T, Koh YW, Lee HK, Petznick A, Tong L. Bioimage Informatics Approach to Automated Meibomian Gland Analysis in Infrared Images of Meibography. J of Optometry DOI information: /j.optom Celik T, Koh YW, Lee HK, Petznick A, Tong L. Bioimage Informatics Approach to Automated Meibomian Gland Analysis in Infrared Images of Meibography. J of Optometry DOI information: /j.optom About the Author Associate Professor Louis Tong is a principal clinician-scientist, head of the Ocular Surface Research Group, co-head of the Ocular Inflammation and Immunology Research group at the Singapore Eye Research Institute, senior consultant ophthalmologist at the Corneal and External Eye Service of Singapore National Eye Centre, and also associate professor at the Office of Clinical, Academic and Faculty Affairs at the Duke-National University of Singapore. He holds a PhD degree from National University of Singapore, and is trained in Singapore and Baylor College of Medicine, USA. His research interests are dry eye, corneal epithelial cell biology, inflammation and meibomium gland dysfunction. 35

SingHealth and A*STAR to advance medical research in diabetes; immunotherapy and drug development; and precision medicine

MEDIA RELEASE SingHealth and A*STAR to advance medical research in diabetes; immunotherapy and drug development; and precision medicine Strategic partnership sees Singapore s largest public healthcare