Professor Stuart Cook
I grew up in Kenya, went to high school at St Edward’s, Oxford and studied medicine at St Bartholomew’s Medical School, London. I did a PhD at the National Heart and Lung Institute, UK and a Postdoctoral Fellowship at Harvard. I then trained in cardiology and sub-specialized in cardiac MRI. I am currently a Professor at Imperial College, London and Duke-NUS, where my team helped define the central role of titin in dilated cardiomyopathy and developed a gene-based test for inherited cardiac conditions that was commercialised by Illumina and is now used in clinical practice. My group discovered a critical role for the IL11 cytokine in fibrosis, inflammation and tissue regeneration, which addressed a major misunderstanding in the published literature. I am the co-founder of Enleofen, a biotechnology company that developed first-in-class antibody therapeutics against IL11. Enleofen’s therapeutic platform was acquired by Boehringer Ingelheim in the largest Biotechnology deal from Singapore in late 2019. The overarching goal of my research is to understand disease mechanisms and to translate basic science discoveries to healthcare.
Find out more about Professor Cook's work.
Cardiomyopathy: molecular genetics and variant interpretation
Working with colleagues from the USA and Europe, my group was involved in the discovery of truncating variation in titin as the commonest cause of dilated cardiomyopathy. My group went on to develop a new approach (now widely adopted) to predict titin variant pathogenicity based on exon usage and variant location. We were the first to describe an effect of titin truncations on cardiac structure and function in the general population, which has now been widely replicated. The laboratory and informatics tools developed by my group have translated to patient care in the UK and around the world. More recently, we identified common, low penetrance polymorphisms in hypertrophic cardiomyopathy (HCM) genes that are specific to Chinese populations, and likely one of the commonest causes of HCM, given the size of the Chinese population.
- Herman DS, Lam L, Taylor MRG, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJR, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. New England Journal of Medicine 2012; 366:619–628. doi: 10.1056/NEJMoa1110186.
- Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, L MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, W Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, R Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Science Translational Medicine. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.
- Schafer S, de Marvao A, Adami E, Fiedler L, Ng B, Khin E, Rackham O, van Heesch S, Pua CJ, Kui M, Walsh R, Tayal U, Prasad SK, Dawes TJW, Ko NSJ, Sim D, Chan LL, Mazzarotto F, Barton PJ, Kreuchwig F, de Kliejn D, Totman T, Biffi C, Tee N, Schneider V, Faber A, Regitz-Zagrosek V, Seidman JG, Seidman CE, Linke WA, Kovalik JP, O’Regan DP, Ware JS, Hubner N, Cook SA. Titin truncating variants affect the heart in health and disease. Nature Genetics, 2017 Jan;49(1):46-53. doi: 10.1038/ng.3719.
- Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H. (2017). Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genetics in Medicine. 19:192-203. doi: 10.1038/gim.2016.90.
- Pua CJ, Tham N, Chin CWL, Walsh R, Khor CC, Toepfer CN, Repetti GG, Garfinkel AC, Ewoldt JF, Cloonan P, Chen CS, Lim SQ, Cai J, Loo LY, Kong SC, Chiang CWK, Whiffin N, de Marvao A, Lio PM, Hii AA, Yang CX, Le TT, Bylstra Y, Lim WK, Teo JX, Padilha K, Silva GV, Pan B, Govind R, Buchan RJ, Barton PJR, Tan P, Foo R, Yip JWL, Wong RCC, Chan WX, Pereira AC, Tang HC, Jamuar SS, Ware JS, Seidman JG, Seidman CE, Cook SA. Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients. Circulation Genomics and Precision Medicine. 2020 Oct;13(5):424-434. doi: 10.1161/CIRCGEN.119.002823.
- Meyer HV, Dawes TJW, Serrani M, Bai W, Tokarczuk P, Cai J, de Marvao A, Henry A, Lumbers RT, Gierten J, Thumberger T, Wittbrodt J, Ware JS, Rueckert D, Matthews PM, Prasad SK, Costantino ML, Cook SA, Birney E, O'Regan DP. Genetic and functional insights into the fractal structure of the heart. Nature. 2020 Aug;584(7822):589-594. Epub 2020 Aug 19. doi: 10.1038/s41586-020-2635-8.
Identification of interleukin 11 (IL11) as a critically important pro-fibrotic gene
Using cardiac fibroblasts from patients undergoing heart surgery, we identified interleukin 11 (IL11) as a major determinant of heart and kidney fibrosis and showed that the earlier literature on IL11 was largely incorrect. We went on to show that IL11 is important for fibrosis across organs and that neutralizing IL11 antibodies can prevent and reverse fibrosis in mouse models of human heart, lung and liver disease. My group went on to show that the IL11 receptor is widely expressed on polarised and epithelial cells and that it regulates parenchymal function, in addition to its stromal effects. We filed over 10 patents relating to IL11 biology, many of which have been granted worldwide, and a subset of which have been licenced by Boehringer Ingelheim. The anti-IL11 antibodies made in my academic laboratory were licenced to Enelofen, a biotechnology company that I founded, that was acquired by Boehringer Ingelheim in 2019. It is anticipated that clinical trials using anti-Il11 antibodies for treating fibrotic human disease will begin in early 2022.
- Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, Tan J, Chothani SP, Ye L, Rackham OJL, Ko NSJ, Sahib NE, Pua CJ, Zhen NTG, Xie C, Wang M, Maatz H, Lim S, Saar K, Blachut S, Petretto E, Schmidt S, Putoczki T, Guimarães-Camboa N, Wakimoto H, van Heesch S, Sigmundsson K, Lim SL, Soon JL, Chao VTT, Chua YL, Tan TE, Evans SM, Loh YJ, Jamal MH, Ong KK, Chua KC, Ong BH, Chakaramakkil MJ, Seidman JG, Seidman CE, Hubner N, Sin KYK, Cook SA. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017 Dec 7;552(7683):110-115. doi: 10.1038/nature24676.
- Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D'Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, Tripathi M, Lim SY, Shekeran SG, Chothani SP, Rabes A, Sombetzki M, Bruinstroop E, Min LP, Sinha RA, Albani S, Yen PM, Schafer S, Cook SA. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Non-Alcoholic Steatohepatitis. Gastroenterology. 2019 May 8. pii: S0016-5085(19)40858-5. doi: 10.1053/j.gastro.2019.05.002.
- Ng B, Dong J, D'Agostino G, Viswanathan S, Widjaja AA, Lim WW, Ko NSJ, Tan J, Chothani SP, Huang B, Xie C, Pua CJ, Chacko AM, Guimarães-Camboa N, Evans SM, Byrne AJ, Maher TM, Liang J, Jiang D, Noble PW, Schafer S, Cook SA. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Science Translational Medicine. 2019 Sep 25;11(511). pii: eaaw1237. doi: 10.1126/scitranslmed.aaw1237.
- Dong J, Viswanathan S, Adami E, Singh BK, Chothani SP, Ng B, Lim WW, Zhou J, Tripathi M, Ko NSJ, Shekeran SG, Tan J, Lim SY, Wang M, Lio PM, Yen PM, Schafer S, Cook SA, Widjaja AA. Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. Nature Commun. 2021 Jan 4;12(1):66. doi: 10.1038/s41467-020-20303-z.