Genomics England and the power of DNA data


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Presentation by Sir Mark Walport at the Wired Health Conference on 29 April 2014.

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  • The speech has three key messages:
    Scientific developments in our understanding of human genetics drive developments in healthcare and medicine. The human genome project marked a step-change in our understanding of human biology: the 100,000 genome project has the potential to be another important milestone.
    Projects like the human genome project and the 100,000 genome project are complex and demanding but the effort is outweighed by the positive consequences for healthcare and quality of life.
    These projects have and will make the UK a world-leader in genomics and genetics but maximising on the potential of these developments requires innovations in the NHS and the ways that healthcare is provided.
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    In 1911 Alfred Sturtevant, an undergraduate made the first genetic map showing the relative locations of genes in the fruit fly. Image 1: historical map showing location of genes in Drosophila
    In 1953 Watson and Crick described the structure of DNA. Image 2: part of Crick’s notebook detailing structure of DNA
    In April 2003, 92 years after the first gene map and 50 years after the structure of DNA was described, the first full human genome sequence showing the location and coding of all of the genes in the human genome was completed and published. This marked a step-change in our understanding of human genetics and the basis of many diseases. [You may wish to link this to 2003 being the year you took over as Director of the Wellcome Trust]. Image 3: Published Genome-Wide Associations through Q1/2013 Published GWA at p≤5X10-8 for 17 trait categories
  • Sequencing the human genome drove huge developments in:
    sequencing technology (image of sequence trace)
    data sharing - open access to human genome data via specialist databases which was agreed during meeting in Bermuda – known as the Bermuda principles (image of Bermuda)
    the expertise of scientists in bioinformatics (data analysis, genome assembly, identification of genes, etc) (sequence alignment)
  • Objectives:
    RESEARCH: Delineate the genetic architecture of severe undiagnosed disorders of infancy and childhood
    TRANSLATION: Optimise ethical implementation of genomic technologies for clinical diagnosis
    A UK-wide collaboration:
    Patients, their families and NHS Genetic Services
    Funded by Health Innovation Challenge Fund (HICF)
    Recruit 12,000 patients and their parents
    Record phenotypes systematically
    Apply microarrays and trio sequencing
    Identify and feedback likely causal variants to RGS
    Share data and facilitate research
    >8,300 patients recruited since April 2011 across whole of UK and Eire
    ~30% diagnosis rate for children with severe developmental disorders where routine investigations were unable to make a diagnosis
    Analysis of first 1,000 families has identified 14 new genes for developmental disorders
    Deciphering Developmental disorder variants are shared in DECIPHER – global matching of variants causing Rare Disease
    Over 500 publications citing DECIPHER in past 5 years
  • Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study
    Simon R Harris PhD a , Edward JP Cartwright MBBS b d , M Estée Török FRCP b d e, Matthew TG Holden PhD a, Nicholas M Brown MD d e, Amanda L Ogilvy-Stuart FRCP e, Matthew J Ellington DPhil d, Michael A Quail PhD a, Stephen D Bentley PhD a, Prof Julian Parkhill PhD a †, Prof Sharon J Peacock FRCP a b c d e †
    The emergence of meticillin-resistant Staphylococcus aureus (MRSA) that can persist in the community and replace existing hospital-adapted lineages of MRSA means that it is necessary to understand transmission dynamics in terms of hospitals and the community as one entity. We assessed the use of whole-genome sequencing to enhance detection of MRSA transmission between these settings.
    We studied a putative MRSA outbreak on a special care baby unit (SCBU) at a National Health Service Foundation Trust in Cambridge, UK. We used whole-genome sequencing to validate and expand findings from an infection-control team who assessed the outbreak through conventional analysis of epidemiological data and antibiogram profiles. We sequenced isolates from all colonised patients in the SCBU, and sequenced MRSA isolates from patients in the hospital or community with the same antibiotic susceptibility profile as the outbreak strain.
    The hospital infection-control team identified 12 infants colonised with MRSA in a 6 month period in 2011, who were suspected of being linked, but a persistent outbreak could not be confirmed with conventional methods. With whole-genome sequencing, we identified 26 related cases of MRSA carriage, and showed transmission occurred within the SCBU, between mothers on a postnatal ward, and in the community. The outbreak MRSA type was a new sequence type (ST) 2371, which is closely related to ST22, but contains genes encoding Panton-Valentine leucocidin. Whole-genome sequencing data were used to propose and confirm that MRSA carriage by a staff member had allowed the outbreak to persist during periods without known infection on the SCBU and after a deep clean.
    Whole-genome sequencing holds great promise for rapid, accurate, and comprehensive identification of bacterial transmission pathways in hospital and community settings, with concomitant reductions in infections, morbidity, and costs.
    UK Clinical Research Collaboration Translational Infection Research Initiative, Wellcome Trust, Health Protection Agency, and the National Institute for Health Research Cambridge Biomedical Research Centre.
  • Diagram of oral cavity and low magnification of small intestine mucosa
  • Since the human genome project, there have been further evolutions in sequencing technology, not just for humans, but also for pathogens. Multiple bacterial genomes can be sequenced in a single run of the sequencing machine. Rather than over a decade, sequencing a human genome now only takes a few days. But these developments are accompanied by ethical issues. In 2012, a study was published in which an entire foetal genome has been sequenced from a sample of maternal blood. Developments such as this underpin the need for ethics to keep up with scientific development. (Ultrasound of foetus)
  • The 100,000 genomes project was launched in December 2012. The project is being run by Genomics England and is funded by the Department of Health. The project will sequence up to 100,000 people or infections within 5 years. Sequencing the whole genome allows a huge range of genetic differences both within coding and non-coding DNA to be identified.
    The sequencing will be focussed on cancers (lung and paediatric), rare diseases and infectious diseases. Combining the sequence data with medical records offers the potential to revolutionise our understanding of the genesis and treatment of some diseases. Linking sequence data with medical information about the patient gives real power to the dataset.
    Rare diseases –Kyphoscoliosis in a 10-year-old girl with HSAN III. Familial dysautonomia (also called hereditary sensory and autonomic neuropathy, type III|) is an autosomal recessive genetic disorder caused by mutations in the IKBKAP  gene. The condition affects the development and survival of certain nerve cells. The disorder disturbs cells in the autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. The IKBKAP gene provides instructions for making a protein called IKK complex-associated protein (IKAP). This protein is found in a variety of cells throughout the body, including brain cells.
    80% of rare diseases are genetic and half of all new cases are found in children. <5% of the population or about 5/10,000 people 3 million people in the UK
    7000 rare disorders- often disabling, shorten life, costly Circa 85% have a single gene defect Testing for >700 disorders extant within the NHS <1/4 of known disease genes. 
    Whole genome sequencing – 25% increase in discovery & diagnostic Will sequence both patients and close relatives
    Cancer (X-ray of lungs showing potential cancer)
    Lung Cancer -40 000 cases/year in the UK, (35K die/year) Therapies modestly effective only applicable to 10-15% of patients - CRUK Stratified Medicine’s initiative
    Breast, colon, prostate, ovary and unknown primary Rare and Childhood Cancers
    Drugs target mutations Tumour heterogeneity
    Pathogens (picture of scanning electron micrograph of Mycobacterium tuberculosis bacteria)
    Stratifying response, minimising adverse events and tracking outbreaks
    M. Tuberculosis resistance and epidemiology Hepatitis C genotype selects therapy HIV –Treatment for life and resistance testing is in the care pathway. Extreme human response to sepsis
  • The scale of the challenge is huge. To be successful, the project will need:
    - Significant funding (£100m funding over the next 5 years) (picture of £1 coins)
    -State of the art sequencing technology with increased capacity, that provides high quality sequence data more cheaply (picture of sequencing machines)
    -New ways of identifying suitable patients and an infrastructure to support sampling, e.g. protocols to collect and transport suitable samples, for example tissue samples from cancers. (Picture of surgery demonstrating that some samples like cancer samples will need to be taken during surgery)
    -Suitable storage and analysis techniques to process and extract meaning from the wealth of data that will be generated through this sequencing. (Picture of computer server)
    -Workforce training – scientists; bioinformaticians; medics; clinical scientists (picture of training course)
    -Consider the ethics of the project. Patients involved will need to make informed consent. Participants may have concerns over allowing commercial companies to access the data but this is necessary to drive developments. (Picture of 12th century byzantine manuscript showing the hippocratic oath)
    -Access of researchers to the data will need to be done securely – e.g. via a secure datalink.
  • The project has huge potential to bring benefits and drive developments such as:
    Improved personalised/stratified medicine
    Faster diagnosis of conditions, especially rare genetic conditions
    Linking genomics to treatment, diagnostics and care.
    Improved pharmaceutical treatments through identification of new drug targets
    Improved disease prevention for example by identifying disease susceptibility
    Stimulating life science research in the UK with positive effects for the economy and wealth of the UK
  • Image is of Trafford Hospital – This Hospital was formerly called Park Hospital and on the 5th July 1948 when all hospitals were nationalised the minister of Health, Aneurin Bevan came to Park Hospital to receive the keys to symbolise the birth of the NHS.
    This is a massive opportunity to drive forward life science research in the UK and abroad. It will build on our current reputation as a world leader in genetics and genomics. But maximising impact for patient treatment and care will need innovation and changes within the NHS.
    Genomics England are working with NHS, academics and industry and funders to drive Genomic Medicine into the NHS
    When the project ends, the NHS will need to be ready to use genomics as part of its routine care. In parallel with the work of Genomics England, a skills and training programme for workers (scientists, geneticists, doctors) in the NHS is currently being set up.
    Leave a legacy of NGS Centres, sample pipeline and biorepository, large-scale data store that makes this usable by the NHS
  • Genomics England and the power of DNA data

    1. 1. Genomics England and the power of DNA data Sir Mark Walport Chief Scientific Adviser to HM Government
    2. 2. 2 Genomics England and the power of DNA data Step changes in genetics and genomics Evolution of medicine and healthcare: How the UK plays a leading role 1911 1953 Since 2003 First gene map Structure of DNA discovered First human genome sequenced Image: Wellcome Library, LondonImage: Wellcome Library, London
    3. 3. 3 Genomics England and the power of DNA data 1911 The human genome project Image: Dan Mason (CC BY-NC-SA 2.0) Image: Miguel Andrade Image: U.S. Defense Imagery Image: Sjef
    4. 4. 4 Genomics England and the power of DNA data Deciphering developmental disorders
    5. 5. 5 Genomics England and the power of DNA data Developments in sequencing can track the transmission of disease Image: Jake Berenguer (U.S. Navy)
    6. 6. 6 Genomics England and the power of DNA data From data to knowledge to societal benefit
    7. 7. 7 Genomics England and the power of DNA data Whole genome sequencing provides information about the microbiome Image: Duncan Kenneth Winter (CC BY 2.0) Image: Nephron
    8. 8. 8 Genomics England and the power of DNA data Challenges and opportunities
    9. 9. 9 Genomics England and the power of DNA data Combining large numbers of human sequences with medical data can drive further developments 100,000 genomes in 5 years Infectious disease Image: NIAID Image: Axelrod FB, Gold-von Simson G (CC BY 2.0)
    10. 10. 10 Genomics England and the power of DNA data The project will face significant challenges and overcoming these will drive developments Image: Images_of_money Image: torkildr (CC BY-SA 2.0) Image: Army Medicine Image: jurvetson (CC BY 2.0) Image: National Data Centre
    11. 11. 11 Genomics England and the power of DNA data This work will bring benefits and drive developments Image: James Cridland (CC BY 2.0) Image: Oscar Diaz (CC BY-NC-SA 2.0) Image: e-Magine Art Image: freeimageslive Mr Jones Mrs Smith
    12. 12. 12 Genomics England and the power of DNA data Maximising impact for patient treatment and care will need innovation and changes within the NHS Image: Dave Smethurst (CC BY-SA 2.0)