IEEE Life Sciences Grand Challenges Conference December 2-3, Singapore U-Town, National University of Singapore THE WANDERINGS OF A FREE RADICAL Professor Barry Halliwell Tan Chin Tuan Centennial Professor Deputy President (Research & Technology) National University of Singapore Life history Year Event 1968 - 1971 Studied Chemistry and Biochemistry at St Catherine’s College, Oxford University 1971 - 1973 Stayed on to do a D.Phil on plant metabolism, University of Oxford Botany School. Studied photorespiration. (a rather well worn topic) 1974 - 1988 Lecturer and subsequently Reader, Biochemistry, Kings College London. 1988 - 2000 Professor, Division of Pharmacology, Kings College London 1995 – 1998 Decided to try something new (one year full time, almost Visiting Research Professor in Internal Medicine and Biochemistry, four years part time) University of California, Davis / Berkeley 1998 - 2000 Decided to try something new again Visiting Professor of Biochemistry, NUS 2000 - 2007 Head, Department of Biochemistry, NUS 2003 - 2008 Executive Director, NUS Graduate School for Integrative Sciences & Engineering 2006 - present Deputy President (Research & Technology) WHAT NEXT? Plants are essential to humans • Supply oxygen • Supply diet-derived antioxidants (ascorbate*, tocopherols*, carotenoids,? Flavonoids?) • Diets rich in plants are associated with lower disease risk (some cancers, diabetes, cardiovascular, dementia) But why? THE LUCK OF THE DRAW BETTER THAN PHOTORESPIRATION ALL ASPECTS OF AEROBIC LIFE INVOLVE FREE RADICALS AND ANTIOXIDANTS – YOU CANNOT ESCAPE THEM, NOR SHOULD YOU WISH TO. Halliwell B. (2006) Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol. 141, 312-22 Oxidant – Antioxidant Balance Peroxiredoxins AA Metabolism Glutathione system Phagocytes SOD, Catalase Diet-Derived Antioxidants Mitochondrial Blood respiration components NADPH oxidases Iron chelators Albumin, DUOxes Caeruloplasmin, Xanthine oxidase Transferrin, haptoglobin etc So some oxidative damage is inevitable and repair &/or replacement of damaged molecules is essential ROS are bad They contribute to many age-related diseases and possibly to the ageing process itself. But they are also good, they help protect against disease in animals and coordinate the inflammatory response, e.g. via redox- signalling, as well as participating in the killing of pathogens. Phagocyte ROS production is a key event. NEURODEGENERATIVE DISEASES ARE ACCOMPANIED BY Amyloid plaques Neurofibrillary tangles 1. Mitochondrial Alzheimer disease Alzheimer disease dysfunction 2. Accumulation of abnormal proteins Lewy Body Inclusion bodies 3. Increased oxidative Parkinson disease Huntington disease damage 4. Iron deposition OXIDATIVE DAMAGE IN ALZHEIMER DISEASE Rises in 8OHdG and other base oxidation products in both nuclear and mitochondrial DNA, also rises in 8OHG, protein carbonyls, glutamic and aminoadipic semialdehydes (protein oxidation products), methionine sulphoxide, nitrotyrosine, acrolein, HNE, HO-1 and IPs in brain tissue. Plaques and paired helical filaments contain oxidized, glycated, and nitrated proteins, and CSF from AD patients is also reported to contain elevated levels of oxidized, nitrated and glycated proteins. One oxidized protein associated with plaques is CuZnSOD. Damage is already elevated in brain tissue and CSF in mild cognitive impairment and early AD. Current Research in the Halliwell Lab 1. Antioxidants in Human Health and Disease 2. Mechanisms of Neurodegeneration 3. Artefacts in Cell Culture 4. Ageing in the nematode C.elegans WHY RESEARCH IN SINGAPORE? South Korea Japan Middle East China India Bangladesh Hong Kong Taiwan Thailand Vietnam USA Europe Sri Lanka Philippines Malaysia Australia Singapore Brunei Advantages • No energy (except some solar) • Location • Little food New Zealand • Political / social stability • Little space • Stable government • No oil or mineral resources Indonesia • People / High level of • Water-constrained education • Climate change • Connectivity • Very small, minute domestic market • Good social coherence • Low reproduction rate • Globally connected means risk of disease / financial crisis etc can impact very fast STRENGTHS OF NUS Research is conducted in All Major Disciplines Faculties and Schools (Undergraduate and Graduate education) 1. Arts and Social Sciences 7. Law 2. Business 8. Medicine 3. Computing 9. Music 4. Dentistry 10. Public Health 5. Design and Environment 11. Science 6. Engineering 12. University Scholars Programme (for Undergraduate only) Graduate Schools 1. Duke-NUS Graduate Medical School 2. Lee Kuan Yew School of Public Policy 3. NUS Graduate School for Integrative Sciences and Engineering RESEARCH INSTITUTES & CENTRES 23 University-level RICs + 3.5 Research Centres of Excellence • Asia Research Institute • Mechanobiology Institute • Cancer Science Institute of • Middle East Institute Singapore • NUS Environmental Research Institute • Centre for International Law • NUS Nanoscience & Nanotechnology • Centre for Maritime Studies Initiative • Centre for Remote Imaging, Sensing • NUS Research Institute in Suzhou & Processing • Risk Management Institute • Centre for Quantum Technologies • Singapore Centre on Environmental • East Asian Institute and Life Sciences Engineering • Energy Studies Institute • Singapore Institute for Neurotechnology • NUS Global Asia Institute • Singapore Synchrotron Light Source • Institute for Mathematical Sciences • Solar Energy Research Institute of • Institute of Real Estate Studies Singapore • Institute of South Asian Studies • Temasek Laboratories • Interactive & Digital Media Institute • The Logistics Institute-Asia Pacific • Life Sciences Institute • Tropical Marine Science Institute *Occupants SINGAPORE’S NATIONAL AND ONLY MIT COMPREHENSIVE UNIVERSITY ETH Zurich TUM Munich Synergy in Proximity Imperial College Hebrew University Technion Israel Berkeley Peking University CREATE Biopolis NUS NTU Others Fusionopolis National University SICS Hospital MRT! one-north Map courtesy of Singapore JTC Corporation Science Parks 15 SICS – Singapore Institute for Clinical Science (A*STAR) Duties of DP(R&T) Office - Administration and Compliance Promote NUS-Industry Exchange - Facilitation Grant Seed Grant Dialogue with Funding Administration Matching Grant Scheme Funders Identify Areas of Strategic Importance High Impact Growing Research the Pie Promote Multidisciplinary Research Programmes Attract & Retain Talent Build solid base of high-quality research across a reasonably-broad range of disciplines Research Strong Global Benchmarking Establish Research Centres of Excellence Profile Review within NUS & other Peaks of International Research and relative to peer Excellence in selected areas universities (research benchmarking) Recognition & Establish International Facilitate Commercialisation Research Networks of Research Outcomes Research Reward of Research Spin Off Excellence Publicise Achievements IP Protection Protection of Research Prestigious Research Awards Integrity Animal Welfare Institutional Review Board (IACUC) NUS CAN NURTURE FOR SINGAPORE NICHE AREAS OF HIGH QUALITY THAT ARE NOT YET THE “FLAVOUR OF THE MONTH” [e.g. non-medical biology, plant science, humanities and social science (e.g. Asia Research Institute), pure mathematics] One example • Molecular basis of crop yields (MOU signed with the International Rice Research Institute (IRRI) on 16 Feb 2009) • Crop resistance to environmental change • Nutrition, diet and health maintenance in Asians • Biodiversity • New competitive grants from NRF and SMF (3 grants totalling $21.2 million were obtained in the food security area) An example of how “basic” research suddenly becomes relevant! BUT SINGAPORE IS VERY PRAGMATIC Demonstrate your value WHAT IS NUS FOR? • Universities in Singapore are complementary to A*STAR research institutes. • One key function of research intensive universities is to provide a strong and broad research base not only to address concerns of today but to create opportunities for tomorrow. • A university PI recruited on the basis of his/her promising and novel research concepts typically begins as Assistant Prof to build his/her research and compete for small grants (<$1M). Over time and with more experience, he/she will develop a unique research niche and also will gain the strength to participate in bigger programmes and consortia. NUS SEEKS TO CONDUCT IMPACTFUL RESEARCH WHAT IS IMPACT OF RESEARCH? • Outstanding fundamental research of high intellectual impact that attracts attention to Singapore as a country capable of performing such research and grows NUS’ global reputation • Research which helps to grow new industries for Singapore and to develop existing ones, e.g. by spin-offs and licensing of Intellectual Property (IP) • Research that helps to attract high-level foreign industry to locate in Singapore • Research that makes Singapore a better place to live and improves the health and welfare of the population • Research that expands intellectual breadth and develops ideas and discourses about human experiences which will prepare us more effectively for an increasingly global and cosmopolitan world • Research that influences and informs government policy • Research that enhances the security of Singapore (e.g. defence, food, energy supply) Note that the best research programmes often contribute in several ways. When I was young, the Free Radical –Antioxidant Field was SIMPLE Free radicals are bad Antioxidants are good Taking antioxidants