Setting up the 100 000 Genomes Project involved the creation of 13 regional centres where tissue samples are collected and processed to extract their DNA. “One of the very important things the project has already done is transform pathways within the NHS”, said Louise Jones, professor of breast pathology at Barts Cancer Institute and Genomics England’s lead for molecular pathology. “It has transformed how we handle patient [pathology] samples. The quality has improved and there is greater consistency in the kind of testing that patients will receive across the country.”

The DNA extracted from participants goes to a central sequencing centre located on the Wellcome Genome Campus at Hinxton near Cambridge.

As Julia Wilson, associate director of the nearby Wellcome Sanger Institute, explained, chopping the DNA of a genome into millions of smaller pieces and reading the order of the bases in each piece is the easy bit of sequencing. “The complicated bit is putting the genome back together again”, she said. Even more laborious is analysing it: looking for patterns of genetic variation and judging their significance. “Computer software packages can help”, she added. But human skill is still required to interpret the findings returned to local genetics centres.

“The 100 000 Genome Project has achieved a lot in a short space of time, and on a scale you do not often see in the NHS where, to be honest, things take a long time to achieve”, said Jones. “It made people adapt very quickly… we are so much further ahead than we were 3 or 4 years ago.”

The new GMS will continue to focus on the genomes of people with inherited disorders, those with cancer, some of their immediate relatives, and some microbial genomes with a view to tracking infectious disease and drug resistance. The more genomes are added to the database, the more it will be possible to identify genetic variants associated with these conditions.

Mark Caulfield, chief scientist of Genomics England and professor of clinical pharmacology at Queen Mary University of London, said: “In cancer, about half of the patients [in the 100 000 Genomes Project] had something in their genome which might pave the way for an opportunity to join a clinical trial or suggest a medicine.”

By way of example, Caulfield described a woman with a breast tumour of a type making her eligible to join the OLYMPIA clinical trial of a poly-ADP ribose polymerase inhibitor, a biological therapy. “Her daughter was also tested”, he said. “She was positive and from her 30th birthday will now get intensive magnetic resonance imaging breast screening.” This would not have happened had her mother’s genome not been analysed to identify the genetic underpinnings of her disease.

Speaking for Cancer Research UK, its head of policy development, Emlyn Samuel, described the goals of the GMS as in line with his organisation’s objectives. In the past, he said, patients who might be suitable for a particular drug have sometimes missed out.

“This service will provide a platform not only to give better access to medicines already approved but to trials testing them. It could represent a fundamental shift in how we provide precision care to patients.”

In the case of inherited disease, the 100 000 Genomes Project has already been able to offer a diagnosis for one in four participants. Jayne Spink, chief executive of the Genetic Alliance UK, a charity that campaigns on behalf of people with genetic disorders, welcomes the advent of the GMS. “One of the issues with rare diseases is the long diagnostic odyssey”, she said. “It is not unusual for a patient to see five consultants and spend 3 years finding a diagnosis and have three or more misdiagnoses along the way. What genomics can offer is a quicker and more accurate diagnosis and help to avoid wrong treatments.”

The value of genomics in most common diseases is currently less clear. Any inherited influence could be mediated not by one or two but possibly hundreds of genes. Jones is undismayed. “On a smaller scale, there are already some research studies looking at that kind of influence, in prostate cancer, for example, and in breast cancer.” She is confident that genomes collected through the GMS will eventually allow us to identify even complex predispositional gene patterns. Caulfield acknowledges that this requires vast computational power. “But it is within our ability to do it”, he said. “Up to 1000 different gene regions influence blood pressure. Combine them and you can predict a 13 mm increase in blood pressure in the over-50s.”

With due caution, Caulfield also accepts the case for gene sequencing at birth. “There are some rare diseases presenting in early life where a whole genome would allow us to prevent some of their consequences. There are people in the programme for whom we have already done that.” But he added a caveat: “This first needs a research programme of its own and a proper societal debate.”

A common lay response to all the professional excitement tends to be one of puzzlement. When hospital waiting lists are lengthening and estimates of the shortfall in funding run into billions, how can the NHS be trumpeting a further leap into the high-tech, high-cost world of molecular medicine? Caulfield meets this head on by emphasising the need for greater efficiency. He talked of a child who had been to the doctor 151 times by his fourth birthday. “He has been through about ten specialties. With tests and admissions, he has cost the NHS £36 000. If his whole genome had been deployed 4 years earlier, we could have avoided at least 20% of those episodes.”

Even so, there is still the hurdle confronting all preventive strategies: promised future savings require an upfront investment. Caulfield insists he can convince health-care providers. “We have already done that in the GMS or they would not be commissioning it now in the NHS.”

Besides issues of funding in general, there are questions over specific resources, both human and technological. Evidence supplied in January to the Commons Science and Technology Committee by the Association for Clinical Genomic Science drew attention to skill shortages. “We believe there is a serious risk of under-capacity in the workforce to deliver the full benefits of clinical genomics reorganisation”, it said. Jones acknowledged the problem but pointed to “the huge push to raise the skill levels of the [NHS] workforce. We have worked with the Royal College of Pathologists to raise the amount of genomic medicine in their training.”

One technological hurdle is mentioned on Genomics England’s own website. Many hospital pathology labs still rely on the formalin preservation of biopsy material from tumours. Formalin damages DNA and is therefore unsuitable for whole genome sequencing. The ideal is freshly frozen material stored at −80°C.

As Genomics England points out, “freshly frozen is more difficult for busy NHS hospitals and clinics. Many do not currently have equipment or infrastructure to do it.” But more are investing in it,” said Jones. “And there are different fixatives, which are also more genome friendly.”

Right now, Caulfield is confident about the future of the GMS (panel) and keen to point out that the UK is well ahead. The project, he said, is already seen internationally as a model. “The NHS rose to the challenge and delivered the programme…Where it can bring real benefit, we will now be able to provide any patient with whole genome sequencing. From the first quarter of 2019, we will be the first heath system on the planet to be doing that.”

Genohype: a valuable driver?

Projects such as the 100 000 Genomes Project and its successor are often accused of hyping their prospects and achievements. The conventional view is that, by promising more than might be deliverable, such declarations ultimately hinder the enterprise. By contrast, social scientists Gabrielle Natalie Samuel and Bobbie Farsides of Brighton and Sussex Medical School have recently suggested that “promissory discourses have become a part and a driver of the project itself”. Writing in the journal New Genetics and Society, they suggest that ambitious goals, high expectations, and tight deadlines can exert a galvanising effect, and drive clinical change to an extent that might otherwise have been impossible.

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