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Stuart Cook

Professor

Email

Contact: 66012584

Dr Cook grew up in Kenya, went to high school at St Edward’s, Oxford and studied medicine at St Bartholomew’s Medical School, London. He did a PhD at the National Heart and Lung Institute, UK and a Postdoctoral Fellowship at Harvard. He trained in cardiology and sub-specialized in cardiac MRI. He is Professor at Imperial College, London and Duke-National University of Singapore (Duke-NUS). He is a cardiologist at the National Heart Centre Singapore where he oversees the clinical MRI service. He is the Director of the National Heart Research Institute Singapore and Program Director of the CVMD program at Duke-NUS. He is co-founder of Enleofen, a biotechnology company developing therapies for the treatment of fibrotic diseases.

His team discovered a critical role for the IL-11 cytokine in fibrosis and inflammation. He is co-founder of Enleofen, a Singaporean biotechnology company developing first-in-class antibody therapeutics for a range of fibro inflammatory diseases of the liver, kidney, heart, lung and bowel. The overarching goal of his research is to understand cardio metabolic disease mechanisms and to translate basic science discoveries to healthcare.

Impact: translation of science for patient benefit

We showed that truncating mutations in the titin gene (TTNtv) are the commonest cause of severe DCM (NEJM, 2012) and of ambulant DCM while unexpectedly prevalent (1%) in the general population (Science Translational Medicine, 2015). We demonstrated haploinsufficiency as the disease mechanism (Science, 2015) and that TTNtv are commonly found in peri-partum cardiomyopathy (NEJM, 2016). We showed TTNtv to be associated with activation of specific signaling pathways and that TTNtv are not silent in the general population (Nature Genetics, 2017). We developed a next generation sequencing assay (JCTR, 2015) that was commercialized by Illumina as the TruSight Cardio Sequencing Kit and highlighted by the British Heart Foundation as one of the Foundation’s research breakthroughs of 2016. The assay, bioinformatics pipeline and rich variant annotations we developed (Genetics in Medicine, 2016; EHJ, 2017) have transitioned in patient care around the world. To disseminate findings further the Group developed automated, web-based variant annotation tools (http://cardiodb.org/titin/) (https://www.cardioclassifier.org/) that are used by researchers and healthcare professionals globally. Recent studies (JACC, 2017, 2018) are beginning to outline how patient stratification based on TTNtv may influence management of DCM.

Impact: commercialisation of research

Research by my Group (2013-2017) identified IL11 as a factor that is critical for cardiovascular fibrosis (Nature, 2017). Several patents have been filed around this innovation and the development of novel biologic agents against IL11. Cook and Schaefer are co-founders of a spinout company Enleofen Bio (www.enleofen.com) that has licensed these patents and secured funding for anti-fibrotic drug development.

Selected Publications:

Lei Ye, Giuseppe D'Agostino, Sze Jie Loo, Chen Xu Wang, Li Ping Su, Shi Hua Tan, Gui Zhen Tee, Chee Jian Pua, Edgar Macabe Pena, Redmond Cheng Belen, Way Cherng Chen, Desiree Abdurrachim, Janise Lalic, Ru San Tan, Teck Hock Lee, Jianyi Zhang, Stuart A. Cook. Early Regenerative Capacity in the Porcine Heart. 20 Jul 2018, Circulation.

James S Ware, Almudena Amor-Salamanca, Upasana Tayal, Risha Govind, Isabel Serrano, Joel Salazar-Mendiguchía, Jose Manuel García-Pinilla, Domingo A Pascual-Figal, Julio Nuñez, Gonzalo Guzzo-Merello, Emiliano Gonzalez-Vioque, Alfredo Bardaji, Nicolas Manito, Miguel A López-Garrido, Laura Padron-Barthe, Elizabeth Edwards, Nicola Whiffin, Roddy Walsh, Rachel J Buchan, William Midwinter, Alicja Wilk, Sanjay Prasad, Antonis Pantazis, John Baski, Declan P O’Regan, Luis Alonso-Pulpon, Stuart A Cook, Enrique Lara-Pezzi, Paul J Barton, Pablo Garcia-Pavia. Genetic Etiology for Alcohol-Induced Cardiac Toxicity. Volume 71, Issue 20, May 2018 DOI: 10.1016/j.jacc.2018.03.462, Journal of the American College of Cardiology.

James S Ware, Stuart A Cook. Role of titin in cardiomyopathy: from DNA variants to patient stratification. Nature Reviews Cardiology volume 15, pages 241–252 (2018)

Sebastian Schafer, Sivakumar Viswanathan, Anissa A Widjaja, Wei-Wen Lim, Aida Moreno-Moral, Daniel M DeLaughter, Benjamin Ng, Giannino Patone, Kingsley Chow, Ester Khin, Jessie Tan, Sonia P Chothani, Lei Ye, Owen JL Rackham, Nicole SJ Ko, Norliza E Sahib, Chee Jian Pua, Nicole TG Zhen, Chen Xie, Mao Wang, Henrike Maatz, Shiqi Lim, Kathrin Saar, Susanne Blachut, Enrico Petretto, Sabine Schmidt, Tracy Putoczki, Nuno Guimarães-Camboa, Hiroko Wakimoto, Sebastiaan van Heesch, Kristmundur Sigmundsson, See L Lim, Jia L Soon, Victor TT Chao, Yeow L Chua, Teing E Tan, Sylvia M Evans, Yee J Loh, Muhammad H Jamal, Kim K Ong, Kim C Chua, Boon-Hean Ong, Mathew J Chakaramakkil, Jonathan G Seidman, Christine E Seidman, Norbert Hubner, Kenny YK Sin, Stuart A Cook. IL-11 is a crucial determinant of cardiovascular fibrosis. Naturevolume 552, pages 110–115 (07 December 2017)

Nicola Whiffin, Eric Minikel, Roddy Walsh, Anne H O’Donnell-Luria, Konrad Karczewski, Alexander Y Ing, Paul JR Barton, Birgit Funke, Stuart A Cook, Daniel MacArthur, James S Ware. Using high-resolution variant frequencies to empower clinical genome interpretation. Genetics in Medicine volume 19, pages 1151–1158 (2017)

Upasana Tayal, Simon Newsome, Rachel Buchan, Nicola Whiffin, Roddy Walsh, Paul J Barton, James S Ware, Stuart A Cook, Sanjay K Prasad. Truncating variants in titin independently predict early arrhythmias in patients with dilated cardiomyopathy. Volume 69, Issue 19, May 2017 DOI: 10.1016/j.jacc.2017.03.530, Journal of the American College of Cardiology.

Roddy Walsh, Kate L Thomson, James S Ware, Birgit H Funke, Jessica Woodley, Karen J McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C Taylor, Eric V Minikel, Daniel G MacArthur, Martin Farrall, Stuart A Cook, Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genetics in Medicine volume 19, pages 192–203 (2017)

Roddy Walsh, Rachel Buchan, Alicja Wilk, Shibu John, Leanne E Felkin, Kate L Thomson, Tang Hak Chiaw, Calvin Chin Woon Loong, Chee Jian Pua, Claire Raphael, Sanjay Prasad, Paul J Barton, Birgit Funke, Hugh Watkins, James S Ware, Stuart A Cook. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. European Heart Journal, Volume 38, Issue 46, 7 December 2017, Pages 3461–3468, https://doi.org/10.1093/eurheartj/ehw603

Sebastian Schafer, Antonio De Marvao, Eleonora Adami, Lorna R Fiedler, Benjamin Ng, Ester Khin, Owen JL Rackham, Sebastiaan Van Heesch, Chee J Pua, Miao Kui, Roddy Walsh, Upasana Tayal, Sanjay K Prasad, Timothy JW Dawes, Nicole SJ Ko, David Sim, Laura LH Chan, Calvin WL Chin, Francesco Mazzarotto, Paul J Barton, Franziska Kreuchwig, Dominique PV De Kleijn, Teresa Totman, Carlo Biffi, Nicole Tee, Daniel Rueckert, Valentin Schneider, Allison Faber, Vera Regitz-Zagrosek, Jonathan G Seidman, Christine E Seidman, Wolfgang A Linke, Jean-Paul Kovalik, Declan O'Regan, James S Ware, Norbert Hubner, Stuart A Cook. Titin-truncating variants affect heart function in disease cohorts and the general population.  Nature Genetics volume 49, pages 46–53 (2017)

Mao Wang, Patrick Sips, Ester Khin, Maxime Rotival, Ximing Sun, Rizwan Ahmed, Anissa Anindya Widjaja, Sebastian Schafer, Permeen Yusoff, Pervinder Kaur Choksi, Nicole Shi Jie Ko, Manvendra K Singh, David Epstein, Yuguang Guan, Josef Houstek, Tomas Mracek, Hana Nuskova, Brittney Mikell, Jessie Tan, Francesco Pesce, Frantisek Kolar, Leonardo Bottolo, Massimiliano Mancini, Norbert Hubner, Michal Pravenec, Enrico Petretto, Calum MacRae, Stuart A Cook. Wars2 is a determinant of angiogenesis. Nature Communicationsvolume 7, Article number: 12061 (2016)

Chee Jian Pua, Jaydutt Bhalshankar, Kui Miao, Roddy Walsh, Shibu John, Shi Qi Lim, Kingsley Chow, Rachel Buchan, Bee Yong Soh, Pei Min Lio, Jaclyn Lim, Sebastian Schafer, Jing Quan Lim, Patrick Tan, Nicola Whiffin, Paul J Barton, James S Ware, Stuart A Cook. Development of a comprehensive sequencing assay for inherited cardiac condition genes. February 2016, Volume 9, Issue 1, pp 3–11, Journal of cardiovascular translational research.

James S Ware, Jian Li, Erica Mazaika, Christopher M Yasso, Tiffany DeSouza, Thomas P Cappola, Emily J Tsai, Denise Hilfiker-Kleiner, Chizuko A Kamiya, Francesco Mazzarotto, Stuart A Cook, Indrani Halder, Sanjay K Prasad, Jessica Pisarcik, Karen Hanley-Yanez, Rami Alharethi, Julie Damp, Eileen Hsich, Uri Elkayam, Richard Sheppard, Angela Kealey, Jeffrey Alexis, Gautam Ramani, Jordan Safirstein, John Boehmer, Daniel F Pauly, Ilan S Wittstein, Vinay Thohan, Mark J Zucker, Peter Liu, John Gorcsan III, Dennis M McNamara, Christine E Seidman, Jonathan G Seidman, Zoltan Arany. Shared genetic predisposition in peripartum and dilated cardiomyopathies. January 21, 2016 N Engl J Med 2016; 374:233-241 DOI: 10.1056/NEJMoa1505517

John T Hinson, Anant Chopra, Navid Nafissi, William J Polacheck, Craig C Benson, Sandra Swist, Joshua Gorham, Luhan Yang, Sebastian Schafer, Calvin C Sheng, Alireza Haghighi, Jason Homsy, Norbert Hubner, George Church, Stuart A Cook, Wolfgang A Linke, Christopher S Chen, Jonathan G Seidman, Christine E Seidman. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science  28 Aug 2015: Vol. 349, Issue 6251, pp. 982-986 DOI: 10.1126/science.aaa5458

Angharad M Roberts, James S Ware, Daniel S Herman, Sebastian Schafer, John Baksi, Alexander G Bick, Rachel J Buchan, Roddy Walsh, Shibu John, Samuel Wilkinson, Francesco Mazzarotto, Leanne E Felkin, Sungsam Gong, Jacqueline AL MacArthur, Fiona Cunningham, Jason Flannick, Stacey B Gabriel, David M Altshuler, Peter S Macdonald, Matthias Heinig, Anne M Keogh, Christopher S Hayward, Nicholas R Banner, Dudley J Pennell, Declan P O’regan, Tan Ru San, Antonio De Marvao, Timothy JW Dawes, Ankur Gulati, Emma J Birks, Magdi H Yacoub, Michael Radke, Michael Gotthardt, James G Wilson, Christopher J O’donnell, Sanjay K Prasad, Paul JR Barton, Diane Fatkin, Norbert Hubner, Jonathan G Seidman, Christine E Seidman, Stuart A Cook. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Science Translational Medicine  14 Jan 2015: Vol. 7, Issue 270, pp. 270ra6 DOI: 10.1126/scitranslmed.3010134

Daniel S Herman, Lien Lam, Matthew RG Taylor, Libin Wang, Polakit Teekakirikul, Danos Christodoulou, Lauren Conner, Steven R DePalma, Barbara McDonough, Elizabeth Sparks, Debbie Lin Teodorescu, Allison L Cirino, Nicholas R Banner, Dudley J Pennell, Sharon Graw, Marco Merlo, Andrea Di Lenarda, Gianfranco Sinagra, J Martijn Bos, Michael J Ackerman, Richard N Mitchell, Charles E Murry, Neal K Lakdawala, Carolyn Y Ho, Paul JR Barton, Stuart A Cook, Luisa Mestroni, JG Seidman, Christine E Seidman. Truncations of titin causing dilated cardiomyopathy. February 16, 2012 N Engl J Med 2012; 366:619-628 DOI: 10.1056/NEJMoa1110186

Chris McDermott-Roe, Junmei Ye, Rizwan Ahmed, Xi-Ming Sun, Anna Serafín, James Ware, Leonardo Bottolo, Phil Muckett, Xavier Cañas, Jisheng Zhang, Glenn C Rowe, Rachel Buchan, Han Lu, Adam Braithwaite, Massimiliano Mancini, David Hauton, Ramon Martí, Elena García-Arumí, Norbert Hubner, Howard Jacob, Tadao Serikawa, Vaclav Zidek, Frantisek Papousek, Frantisek Kolar, Maria Cardona, Marisol Ruiz-Meana, David García-Dorado, Joan X Comella, Leanne E Felkin, Paul JR Barton, Zoltan Arany, Michal Pravenec, Enrico Petretto, Daniel Sanchis, Stuart A Cook. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function. Nature volume 478, pages 114–118 (06 October 2011)

Matthias Heinig, Enrico Petretto, Chris Wallace, Leonardo Bottolo, Maxime Rotival, Han Lu, Yoyo Li, Rizwan Sarwar, Sarah R Langley, Anja Bauerfeind, Oliver Hummel, Young-Ae Lee, Svetlana Paskas, Carola Rintisch, Kathrin Saar, Jason Cooper, Rachel Buchan, Elizabeth E Gray, Jason G Cyster, Peter Braund, Jay Gracey, Unni Krishnan, Jasbir S Moore, Chris P Nelson, Helen Pollard, Tony Attwood, Abi Crisp-Hihn, Nicola Foad, Jennifer Jolley, Heather Lloyd-Jones, David Muir, Elizabeth Murray, Karen O’leary, Angela Rankin, Jennifer Sambrook, Tiphaine Godfroy, Jessy Brocheton, Carole Proust, Gerd Schmitz, Susanne Heimerl, Ingrid Lugauer, Stephanie Belz, Stefanie Gulde, Patrick Linsel-Nitschke, Hendrik Sager, Laura Schroeder, Per Lundmark, Ann-Christine Syvannen, Jessica Neudert, Michael Scholz, Panos Deloukas, Emma Gray, Rhian Gwilliams, David Niblett, Jeanette Erdmann, Christian Hengstenberg, Seraya Maouche, Willem H Ouwehand, Catherine M Rice, Nilesh J Samani, Heribert Schunkert, Alison H Goodall, Herbert Schulz, Helge G Roider, Martin Vingron, Stefan Blankenberg, Thomas Münzel, Tanja Zeller, Silke Szymczak, Andreas Ziegler, Laurence Tiret, Deborah J Smyth, Michal Pravenec, Timothy J Aitman, Francois Cambien, David Clayton, John A Todd, Norbert Hubner, Stuart A Cook. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature volume 467, pages 460–464 (23 September 2010).