Science at scale Highlights 2017/18 Contents 02 What we do 03 Director’s Introduction 04 Wellcome Sanger Institute at a Glance What we do 25 years of 08 Our work pushing the 10 Cancer, Ageing and Somatic Mutation Our work boundaries of 18 Cellular Genetics breakthrough science 22 Human Genetics Our approach 28 Infection Genomics 34 Malaria Other information Other 40 Our approach 42 Scale 44 Innovation Through our big and bold ideas, scientific independence and 46 Culture cutting-edge infrastructure, we engage in long-term exploratory 48 Influence projects that influence science and impact people’s lives on 50 Connections a global scale. 52 Other information 52 Image Credits 53 Institute Information Wherever you see this dark blue text or yellow, click to find sanger.ac.uk more information. Wellcome Sanger Institute Highlights 2017/18 1 What we do Director’s Introduction his year the Wellcome Sanger Institute celebrates its 25th Anniversary. T We have come a long way in that time: from helping to deliver the first reference human genome to asking bold questions about the genomics underlying health and disease. We are proud of our past, but excited about our future. The influence of genomics has progressed in the same way, with society and the What we do NHS embracing genomic technology to transform medicine and lifestyle. While the interrogation and interpretation of genomes, once the field solely of data specialists, is now being carried out by schools across the UK. This remarkable shift is encapsulated in Genome Decoders: Whipworm a pioneering collaboration Our work between Connecting Science, Sanger researchers, the Institute for Research in Schools and school students. Our researchers are now able to interrogate an adult genome to understand its entire mutational history all the way back to the 4-8 cell stage of the embryo and discern Our approach the injuries and insults suffered by the genome on the way. They survey and understand the landscape of diversity and mutation within species spread across countries and continents to discern the rise of antibiotic and pesticide resistance. They develop new techniques to create new models of disease that more closely information Other mirror the human condition. Our scientists are setting new challenges and goals that seem as impossible now as sequencing the Human Genome Project did just 25 years ago. In scale: from the Human Cell Atlas – that aims to unpick the entire human body cell by cell – to sequencing the genomes of all life on earth. In new scientific fields: such as synthesising genomes. In health: from developing early warning systems for infectious disease outbreaks to penetrating malaria’s ever-changing defensive coat to produce effective vaccines and treatments. As we look to the next 25 years, the Sanger will continue to evolve its science focus to navigate and lead in these emerging fields. Professor Sir Mike Stratton, Director Wellcome Sanger Institute 2 Wellcome Sanger Institute Highlights 2017/18 Wellcome Sanger Institute Highlights 2017/18 3 At a Glance 2017 timeline Year in numbers Apr 558 5.203 2018 Sequencing centre In 2017, we read The human Petabases Institute outputs approx. the genomes of genome is approx. 4.639 Pb publications Sanger responds to in 2017 5,400bn 3bn Government Life Sciences Industrial DNA bases a day 547 First mutations bases long strategy different species in life discovered 3.025 Pb Sequencing See page 13 What we do Cell We read centre produces 4 the equivalent the equivalent of Hidden MRSA of one gold-standard 420 14 new childhood outbreaks Nature 1.910 Pb (30x) human genome every developmental 2/3rds 18 gold-standard disorders found detected by (30x) human Malaria needs Takeda joins Open 24 mins routine genomic Nature Genetics 1.054 Pb genomes a by DDD 2/3rds of its genes Targets initiative 27 Isolated Our work for growth surveillance See page 44 week See page 22 Greeks reveal See page 35 See page 30 New England healthy heart NIHR funds Global Journal of Medicine 2 secrets Health Research Unit £20 See page 50 Science See page 25 7 Jan 2015 Jan 2016 Jan 2017 Jan 2018 cing Insecticide uen Cen million Richard Durbin q tr Professor Ele resistance Se e recognised with Our approach Sanger wins Zeggini becomes Royal Society’s in African £20 million CRUK a World Gabor Medal mosquitoes Grand Challenge Economic Forum mapped See page 12 Young Scientist See page 34 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Who published Where Sanger How much DNA our work? staff are from* was sequenced? information Other Cancer knowledge Dr Matt Hurles Number of banks are feasible elected to mutations needed See page 16 Academy of for cancer Medical Sciences discovered Dr Sarah New human cell See page 11 D Teichmann made model reveals HipSci delivers Modern genomes ata ntre Helmholtz chlamydia drug UK’s largest show Biblical Human Cell Atlas 25 Genomes to Ce International Fellow data from first targets human stem Caananites Type 2 be sequenced See page 29 cell resource 1 million cells survived diabetes test to celebrate See page 20 announced See page 18 25 years See page 26 may misdiagnose African Americans See page 49 1,190 See page 25 Europe New malaria Inflammatory Usable storage Bowel Disease 20,000 in the Data centre vaccine suspects pinpointed 62 centre-based target found See page 23 North high performance 9 55PB See page 37 America compute cores Middle 115 East 16 Asia Pacific Total number of Africa compute cores 10 6,000 160GB/sec Latin America 26,000 cloud-based flexible Network backbone compute cores speed * In December 2017 4 Wellcome Sanger Institute Highlights 2017/18 Wellcome Sanger Institute Highlights 2017/18 7 Our work With secured funding from Wellcome, we are able to strategically focus our work in five key research fields 10 Cancer, Ageing and What we do Somatic Mutation Provides leadership in data aggregation and informatics innovation, develops high- throughput cellular models of cancer for genome-wide functional screens and drug testing, and explores somatic mutation’s role in clonal evolution, ageing and development. Our work 18 Cellular Genetics Explores human gene function by studying the impact of genome variation on cell biology. Large-scale systematic screens are used to discover the impact of naturally-occurring and engineered genome mutations in human Our approach iPS cells, their differentiated derivatives, and other cell types. 22 Human Genetics Applies genomics to population-scale studies to identify the causal variants and pathways Other information Other involved in human disease and their effects on cell biology. It also models developmental disorders to explore which physical aspects might be reversible. 28 Infection Genomics Investigates the common underpinning mechanisms of evolution, infection and resistance to therapy in bacteria and parasites. It also explores the genetics of host response to infection and the role of the microbiota in health and disease. 34 Malaria Integrates genomic, genetic and proteomic approaches to develop and enhance high-throughput tools and technologies to study specific biological problems relevant for malaria control and to understand the fundamental science of the human host, the mosquito vector and the Plasmodium pathogen. 8 Wellcome Sanger Institute Highlights 2017/18 Wellcome Sanger Institute Highlights 2017/18 9 Our work Cancer, Ageing and Somatic Mutation 2 The results have profound implications. How cancer evolves Since somatic cells have such a remarkable tolerance of mutations, the findings highlight Number of mutations needed Cancer, Ageing nnovative methods adapted from the important role of individual mutations to cause cancer evolutionary biology have provided a in cellular and organismal ageing. Inew way of viewing cancer development. and Somatic The findings have wide-ranging implications The team discovered that out of the many 6 for our understanding of cell ageing, accumulated mutations acquired over the hunt for cancer driver mutations, a person’s lifetime just one to ten key Mutation and precision oncology. alterations in a cell are required to cause cancer, depending on the tumour type. Cancers can be seen as models of 4 The results also reveal that approximately evolution in action, with cancer cells What we do half of positively selected driver mutations evolving as they accumulate genetic are not in genes previously implicated in changes that provide a selective growth cancer, suggesting that many cancer- advantage. Now that abundant cancer driving changes remain to be discovered. 6 genome sequence data are available, Sanger scientists have seized the In addition, these methods provide a way 16% opportunity to study populations of to assess whether or not specific mutations cancer cells with the same approaches 1 of patients had are truly driving cancer – an essential step 4 mutations affecting developed to explore the evolution of in generating the robust knowledge base Our work the PI3K signalling populations of organisms. that will be needed to apply genomics to Bone cancer pathway clinical decision making and deliver an era In a landmark study published in Cell, of precision oncology. Sanger researchers interrogated data from 2 drug leads more than 7,500 cancers across 29 cancer types.1 Remarkably, species and cancers evolve in diametrically opposed ways. Applying two of the Sanger Institute’s key strengths Species evolution is typically characterised Reference 1. Martincorena I et al. Universal patterns of Our approach – long-term collaboration and whole-genome analysis by negative selection – the loss of mutations selection in cancer and somatic tissues. 11 because they lower fitness. Yet this is hardly Cell. 2017; 171: 1029–1041.e21. – to rare bone cancers has revealed how existing ever seen in cancer. Instead, cancer drugs may offer new treatment options. development is dominated by positive selection – preserving the handful of driver hordoma and osteosarcoma have Similarly, the largest whole-genome mutations that give a cell a competitive been the latest two cancer types sequencing study yet undertaken in growth advantage.