Genomics England was born on the 65th birthday of the UK’s National Health Service (NHS). The NHS is a peerless service and institution in the world; a nationalised, comprehensive and universal healthcare system and one the greatest social reforms of the post-war era. Initially the brainchild of visionary MP Aneurin Bevan, it was built around 3 core socialist principles: To meet the needs of all citizens, to be based on clinical need not social nor financial standing and to be free at the point of delivery. 

In 2013, then Prime Minister, David Cameron set forth a mandate to place the NHS at the forefront of global healthcare by establishing the world’s first national genome project, the forerunner to the application of genomic medicine universally across every one of the UK’s 65 million residents. To this end, Genomics England was established as a company under the management of the Department of Health.

Cameron had been inspired toward this paradigm shift following the death of his son, Ivan, aged 6, four years earlier. Ivan had been born with cerebral palsy and a form of severe epilepsy called Ohtahara Syndrome both rare, incurable genetic disorders.

Rt. Hon. Jeremy Hunt, Secretary of State for Health and Social Care said at the time: “The NHS has a long track record as a leader in medical science advances and it must continue to push the boundaries by unlocking the power of DNA data. The UK will become the first ever country to introduce this technology in its mainstream health system – leading the global race for better tests, better drugs and above all better, more personalised care to save lives. Genomics England will provide the investment and leadership needed to dramatically increase the use of this technology and drive down costs.”

Genomics England is funded by the Department of Health & Social Care. and any surplus will be invested back into improving healthcare. Initially its focus is the completion of the UK 100, 000 Genome Project (UK100KGP), which seeks to sequence the genomes of patients with cancer and rare disease and their healthy relatives. At its inception it seemed immensely ambitious, the kind of enterprise which had never been attempted before. Five years on, it still does.

Chaired by Sir John Chisholm, former chair of the Medical Research Council, who said: “This project represents a great opportunity to translate our world class genomic science into world leadership in genomic medicine. Genomics England will create a dataset of anonymised whole genome sequences matched with clinical data at a scale unique in the world. Participating patients will have the opportunity to benefit from clinical insights derived from the sequencing of their genome while at the same time contributing to knowledge which will be valuable to the whole patient community. It is from that knowledge that world leading therapeutic products and processes will become available to all patients.”

The Department of Health & Social Care chose to establish Genomics England, which frankly, should be called Genomics Great Britain, as a subsidiary limited company because, to have established it as an agency or a public body, would have required primary legislation such as an act of Parliament.

How & Why?

Genomics England was created with four core aims: to bring benefits to all patients, to create an ethical and transparent programme, and to enable new scientific discovery and medical insights and to kickstart the development of a UK genomics industry.

The 100K Genomes Project is not about sequencing 100,000 different patients but 100,000 different genomes. Specifically, the study looksed at; two genomes from every cancer patient with one coming from them and one coming from their cancer, three genomes from each rare disease family with one from the afflicted individual and two more from close blood relatives such as parents. So the actual numbers are around 75,000 people sequenced of whom around 40,000 are patients.

The number was chosen based on experience from the 2010 Sanger Institute study known as the UK10K which sequenced 4,000 healthy individuals and 6,000 with extreme or undiagnosed health problems. The project succeeded in building the foundations for future genomic studies. It built databases of gene interactions and pathogenicity as well as identifying inumerable variants and giving a clearer understanding of the challenges which would face the world’s first national genomic medicine system. This has gone on to form the blueprint for all subsequent large scale genome studies.

Founded by members of the UK10K, including the Primary Investigator, Prof. Richard Durbin, Congenica developed their clinical genomics decision support platform Sapientia out of that research and work done by Prof. Matt Hurles on the Deciphering Developmental Disorders Project, which identified 80,000 genomic variants from exome sequencing and microarray analysis.

In the intervening years, the cost of sequencing has fallen and knowledge about rare variants has increased, thus 100,000 genomes was selected, as the right balance between cost and benefit for NHS patients, with which to build a clinical and research legacy.

Transformation

The 100,000 Genomes Project is not simply a research project. It is a transformation project using genomic medicine to change how NHS patients are treated.  It is transforming healthcare from the modern model in a paradigm shift as big as the introduction of radiology or penicillin. It is transforming the research and findings of the UK10K into actionable results for the populace. These facts alone will transform the NHS and thusly transform Britain into the world leader for life sciences and healthcare but also the owner of the only socially accountable, universal healthcare system anywhere in the world.

Rare diseases aren’t as rare as is commonly conceived, affecting, as they do, 1 in 17 worldwide, over 6% of the global population - half a billion people. In 2014, 163, 444 people in the UK died of cancer, in 2015, 359,960 new cases were reported and the UK has a further 3.5million rare disease sufferers. The legacies of UK100KGP will be most acutely felt by some of the youngest and oldest patients on the NHS. This is because, the risks of cancer increase significantly as you get older and as a nation we are living longer with every generation. In the case of the youngest, it is here that genomics has the greatest life saving potential as 80% of rare diseases manifest in children and, tragically, most of them won’t live to see their 5thfifth birthday.

As the UK100KGP draws to a close in the first half of this year and the company prepares to change its focus to a more traditional business model, it will trade on access to the anonymised data held in the Genomics England Secure Data Centre with research organisations and commercial entities. To aid in this shift, they recently announced the appointment of a new CEO. Taking over from former Chairman, Sir John Chisholm, is Prof. John Mattick, previously of the Australian based Garvan institute of Medical Research, is focusing on this next stage in the life cycle of Genomics England.

Innovative Britain

Britain has always led the world in scientific breakthroughs and DNA was no exception. Crick and Watson won the Nobel Prize for discovering the double helix structure of DNA alongside the too-oft ignored Rosaline Franklin. It was a British scientist, Fred Sanger, who discovered how to sequence it, winning two Nobel Prizes in the process. Now there is the very real opportunity to turn these discoveries into a life-saving reality for NHS patients. A pedigree and mentality of innovation and an understanding of the public good overriding the profit motive have long personified British innovation and the genomic revolution is no different.

Within genomics, researchers and clinicians need as much data as possible and there is no shortage of it. Each person’s genome contains 3.2billion individual letters, nucleotides, within which a single change could result in a devastating pathogenicity. The NHS has lots of supporting data too, this data includes test results, scans, medicines administered, the age at which a person developed particular symptoms and so on. They continue to collect it so they can keep monitoring how a condition progresses over time. This information is important because even small differences in symptoms between individuals might be crucial in finding the changes in their genomes and helping to decide the best treatments.
 

Beginning with a Bake-Off

In the Spring of 2014 Genomics England began taking its first steps towards their bold vision with what was branded the, ‘Genomics England Bake-Off’. This initial phase, named in reference to the popular BBC cookery competition, saw 28 companies compete to find the variants within 15 trios. These companies ranged from industry giants such as Illumina to start-ups, then, still in their infancy such as Congenica.

Of these competitors, 10 were selected in October of that year based upon their ability to quickly and accurately identify the variants known to be in the trios. This pool would reduce further as the four most exciting and effective prospects were given a grant to further develop their ground breaking software platforms. They became Genomics England’s Clinical Interpretation Partners, a validation against their peers thatwhich gave enormous credibility to their tools.

Amongst these companies was Cambridge based, Congenica, and their clinical genomics decision support platform Sapientia. Founded by key members of the 10KGP and DDD, Congenica grew quickly drawing expertise from the private and public sectors and spearheading innovation. Previous diagnostic methods had often been phenotype driven discovery of genetic causes in cases of monogenic disorders but now doctors and clinicians were able to demonstrate the power of their unbiased genotype driven approach and were able to apply this further to identify subsets of patients with similar disorders.

Counting 6 of the world’s leading genome scientists amongst their founders, Congenica came into being after they were inspired to attempt to eliminate the arduous diagnostic odyssey experienced by the majority of rare and inherited genetic disease patients. Using traditional testing methods and consulting strategies, it can take 7 cliniciandoctors 5 years to reach a diagnosis but with Sapientia they had found a way to reduce this to 1 clinician doctor and just 5 days on average. A life changing, and often life saving, difference for patients and their families. Sapientia forms part of the front-line services delivering robust and reliable diagnoses in a rapid manner reducing the anxiety of patients, empowering doctors and reducing costs for healthcare providers.

Implementation

Within the Genomics England ecosystem the aim is to analyse and constantly refine the clinical interpretation of the 100,000 genomes dataset. Clinical interpretation is the next step for the data after the whole genome sequencing, annotation and integration of existing phenotypic data is completed. Through data linkage, this dataset will develop into a rich resource of longitudinal life-course data that is continually augmented and refreshed over time. The goal is to create a truly unique resource in its number of subjects and its breadth of variables.

Genomics enables healthcare professionals to collect associated data in the form of secondary and tertiary findings. These findings may not have direct relevance for the health condition under investigation but, may affect:; medication options, reproductive choices or future medical conditions which are yet to manifest. Implicit in this too is the potential impact one person’s data may have on the patient population as a whole as with every bit of data added to our collective knowledgebases, the more powerful the science becomes.

The raw sequence data from one genome is about 200GB. This mountain of data needs to be interrogated, annotated and presented in a way that is helpful to doctors and clinicians. Here lie Sapientia’s greatest strengths, as this mass of genomic data is uploaded into the system’s ISO-certified, secure, cloud based environment and the variants within it automatically presented in an intuitive integrated genome browser with pedigrees, pathogenicities and known HPO terms all displayed alongside them. From here specialists can further annotate or interrogate the genes in question, can seamlessly search for supporting publications and hold asynchronous multi-disciplinary meetings.

Field programmable gate arrays and automated secondary and tertiary bioinformatics pipelines ensure that the process is a fast as possible and Sapientia is currently the only platform available able to return results against both the established GRCh37 and the most recent GRCh38 reference genomes.

To make genomics a reality for the NHS it has to be of high quality, fast and affordable with results that are readily understood and these values are encapsulated in the Sapientia platform.

Deployment

Now, two years on, Congenica are involved in a number of ground breaking research projects, including…  with major organisations such as Science Foundation Ireland and their joint effort to add the diagnosis of somatic epilepsy to their list of abilities. Sapientia is deployed across Europe, in the United States with such high profile clients as the New York Genome Center and in China through the partnership with Chinese sequencing giant, Beijing Genomics Institute.

In the UK, it was at Manchester’s Centre for Genomic Medicine that Sapientia saw its first live deployment within the NHS. In their Ophthalmology lab in particular they were able to go from offering genetic testing in around 10% of cases to offering it universally.

Now, as the UK100,000K GP enters its final stages, Sapientia is deployed and routinely used in the majority of  6 of the NHS’s 13 Genomic Medicine Centres, where it has been simple to integrate into existing systems, has returned thousands of actionable clinical results and made a tangible difference in treatment or diagnosis to over 450 individual patients. whose cases would have seen little or no progress otherwise.

Legacy

This common approach ensures consistency and coherence across the NHS to gain maximum benefits from the application of genomic technologies, curation of knowledge, and is laying the foundations for the future. The UK is increasingly recognised worldwide as a leader in genomics and the unique structure of the NHS is allowing for these advances to be delivered at scale and pace for patient benefit. The 100,000 Genomes Project is cementing the NHS’s position as one of the most advanced healthcare systems in the world, and is providing the foundation for a new era of personalised medicine, and this in turn will contribute towards the delivery of high quality care for all, now and for future generations.

The list of additional findings for will also change over time asbecause new evidence becomes available about the role of genes in disease. Any findings will be fed back to the NHS, to confirm the result. The structure of the NHS makes it much easier to know much more about the patient in question; details like their symptoms and when they first started, along with physiological measurements, such as heart rate or blood pressure.  Another set of information which may be important in interpreting genomic data comes from their past medical records. The way in which the NHS is able to link a whole lifetime of medical records with a person’s genome data on a large scale is unique.

It is not just patients and the NHS that stand to benefit from the 100,000 Genomes Project. There will be numerous knock-on advantages for the country. Benefits such as new medicines and diagnostic tests some of the companies that may develop will be unexpected, built on new, as yet undiscovered technologies that will emerge over the next five years. The UK, which not only leads the world in life sciences but has the unique benefit of the NHS, is the best place in the world to initiate the practical use of genome sequencing and interpretation for patient benefit. Their vision was one where Britain is the leader in a new industry where genomics is used to help patients get better, more personalised care and treatment.

Genomic England’s legacy will be a genomics service ready for adoption by the NHS, high ethical standards and public support for genomics, new medicines, treatments and diagnostics and a country which hosts the world’s leading genomic companies. It is a bold ambition with benefits for all.