Copyright Lancet
Beyond the 100 000 genomes
The 100 000 Genomes Project showed that countrywide genomic screening infrastructures could be sustainable. Now this could become the norm for the NHS. Geoff Watts reports.
December has seen the 100 000 Genomes Project reach the target number announced by former Prime Minister David Cameron in 2012. But the counter displayed on Genomics England’s website will be allowed to run on. Plans first announced in October by the Secretary of State for Health and Social Care have raised the number of genomes to be sequenced in the next 5 years to 1 million, with an aspiration to reach 5 million.
A project set up principally as a pilot scheme for creating and testing a genetics infrastructure for the National Health Service (NHS), but with the bonus of direct clinical benefit to some participants, is undergoing a transformation. Genomics England now speaks of the NHS Genomic Medicine Service (GMS). And while the penetrance of the nascent service will, for now, remain low as far as everyday health care is concerned, the clinical benefits of the enterprise should move evermore centre stage.
The 100 000 Genomes project: an ambitious project
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.”
Looking towards the GMS
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.”
Expanding the approach to more diseases: is this useful?
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.”
Looking to the future acknowledging the limits of the present
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.
Article Info
Publication History
Published: 05 January 2019
Copyright
© 2019 Elsevier Ltd. All rights reserved.
Copyright Novo Nordisk
Friday, 21 December 2018
The National Genome Centre will analyse blood tests with a view to decoding the DNA sequence of each individual patient. This will create a platform for improving diagnosis and personalized treatment.
Recent advances in technology have opened up new opportunities for mapping and analysing our genes, presenting major opportunities for improving the treatment of patients.
Information about an individual’s genome is the key to developing personalized medicine and tailored treatment that can benefit patients throughout Denmark.
Based on an application by Denmark’s Ministry of Health, the Board of Directors of the Novo Nordisk Foundation has approved a framework grant of DKK 990 million (€133 million) over 4.5 years for establishing and operating the infrastructure of the National Genome Centre. The Foundation has awarded DKK 102 million of this to begin setting up the Centre’s data and information technology unit immediately in 2019.
In addition, the Foundation has awarded a grant of DKK 30 million to enable the Ministry to involve leading experts from Denmark and elsewhere in preparing a resilient project plan for establishing and operating the infrastructure of the Centre.
The goal is for Denmark to become one of the leading countries in this field, improving both the treatment and prevention of disease.
“The Foundation has decided to support the National Genome Centre to create opportunities for improving and targeting treatment services for numerous disease areas to benefit individual patients,” says Lars Rebien Sørensen, Chairman, Novo Nordisk Foundation, adding: ”We have a unique opportunity to set the pace for using this new knowledge about our genes to help doctors in combating disease and saving people’s lives.”
Ellen Trane Nørby, Minister for Health, says: ”The grant from the Foundation for the National Genome Centre can help us accelerate the process by which our healthcare system will increasingly treat people based on knowledge about their genes. This means that doctors can determine which treatments will benefit patients and which will not. For example, we may be able to intervene preventively to benefit a person with inherited heart disease and not simply benefit this person but also their sister, brother, children, father and mother. The grant from the Foundation will contribute to Denmark being able to improve the overall initiatives in personalized medicine to a level that would otherwise take a long time to achieve in Denmark’s healthcare system. This will benefit patients.”
As a result of the initiative, genome sequencing facilities will be established in Aarhus and in Copenhagen as specified in the Ministry’s application. The Ministry expects that about 60,000 people will undergo whole-genome sequencing in the first 5 years of the Centre. The sequencing and data processing will be based at public institutions, and the Centre will give highest priority to security in storing and using the data in a central national database. An interpretation unit will support doctors in using the data to benefit patients.
About the National Genome Centre
The National Genome Centre is an independent organization under Denmark’s Ministry of Health. The Centre will be a hub for the visionary and balanced development of genomic medicine in Denmark. The Government of Denmark allocated DKK 100 million (€13 million) in the 2017 Finance Act to co-finance the work with personalized medicine for 2017–2020.
The Centre’s task is to develop and operate a unified nationwide infrastructure for processing genetic information.
An important goal for the Centre is to collaborate with the healthcare system in all five administrative regions to create the basis for improving diagnosis and targeted treatment to benefit each individual patient.
Further information
Se presentasjonen fra møte i NSG
Christian Mostrup Scheel, Senior Press Officer, phone: +45 3067 4805,
cims@novo.dk
NEW YORK (GenomeWeb) – Two pilot genomic platforms — one serving northern France, the other serving the south — will begin sequencing patient samples in the first quarter of next year as part of the country’s national personalized medicine project.
The establishment of the platforms is a milestone for the Plan France Médecine Génomique 2025 (PFMG), a €670 million ($764 million) initiative the French government
announced two years ago. The new platforms, outfitted with Illumina NovaSeq instruments, are each expected to generate roughly 18,000 genomes from patient samples by 2021, data that will be stored in a centralized database and will inform future research.
«By the first quarter of 2019, we will be fully operational and producing sequences,» said Jean-Yves Blay, director of Centre Léon Bérard, a comprehensive cancer center based in Lyon in southern France.
«The data will be generated at one hospital in Lyon and curated and analyzed by multiple institutions,» Blay said. «All data will be sent to a central repository in a single place, and this will become a public resource for both researchers and private partnerships.»
Blay is the scientific manager for Auragen, one of the two pilot platforms that will begin operations next year. The consortium includes participants from four university hospitals in the region: CHU de Clermont-Ferrand, CHU Grenoble Alpes, Hospices Civils de Lyon, and CHU de Saint-Etienne. In addition, it counts two cancer centers, the Centre Jean Perrin and the CLB, and a cancer research institute, Institut de Cancérologie de la Loire Lucien-Neuwirth, among its members.
The sequencing platform is housed and administered by the genetic service of Hospices Civils de Lyon. Informatics and other reference tools will be coordinated by the CLB for cancer genomes and by CHU Grenoble for genomes associated with constitutional diseases.
Blay noted that Auragen received €150 million of the initial €670 million investment in PFMG to fund its operations through 2025. The Auragen platform is expected to produce 18,000 genomes — 9,000 related to cancer, 9,000 for rare diseases — within its first two years of operations.
The specific indications handled by the center — cancers or rare diseases of interest — are under discussion. Still, Blay noted that by commencing its sequencing operations, whole-genome sequencing will for the first time become universally available to all patients across France.
«France has had whole-genome sequencing installed for the past decade, but following this plan, we will have easier access to this infrastructure to help patients,» Blay said.
Under the original PFGM plan announced in 2016, France was supposed to support a dozen sequencing platforms like Auragen. However, two years into the project and with just two pilot sequencing platforms ready to come online, Blay suggested that there may be fewer platforms in operation by 2025 than originally envisioned.
«My impression is that we have to adapt to the context, which is rapidly evolving,» said Blay. «In 2025, we will certainly have a large data repository, informed by two platforms, perhaps others.»
The other platform that is set to begin operations next year is the Sequencing Omics Information Analysis (SeqOIA) cooperative health group, which involves Assistance Publique-Hôpitaux de Paris, the Institut Curie, the Gustave Roussy Cancer Center, and Institut Imagine. In July, SeqOIA selected Integragen as its industry partner for the project. The company, based in Evry, a suburb of Paris, said in a statement at the time that it would receive €18 million over the next five years to provide SeqOIA with access to exome as well as whole-genome and RNA sequencing data from patients with cancer and rare diseases.
Dominique Stoppa-Lyonnet, the head of the department of genetics at Institut Curie, said that the introduction of the SeqOIA and Auragen platforms in France will create infrastructure that will change the way sequencing has been used in medical genetics in the country to date.
«NGS is implemented in many genetics laboratories already,» Stoppa-Lyonnet noted, «but it is mainly used for multigene panel analysis. The idea of the 2025 plan is to introduce it for whole-genome analysis, as well as for exomes, also.»
Echoing CLB’s Blay, Stoppa-Lyonnet said it was unclear if the country would see a dozen platforms like the ones run by Auragen and SeqOIA in operation by 2025. However, she said it is likely that other platforms will be developed to more directly serve other parts of France. She noted that currently, SeqOIA will serve labs across northern France, in cities like Brest, Rouen, and others, while Auragen will sequence samples for labs across the south in cities like Nice, Marseilles, Toulouse, and Bordeaux. «Labs in these cities use NGS for multigene panels and some for exomes, but very few are able to do whole-genome sequencing yet,» she said.
Another issue that France will confront as its pilot platforms begin to generate sequence data is its clinical utility, Stoppa-Lyonnet pointed out. «Analysis of whole-genome data is still limited,» she said. «But in a few years’ time, it may be easier.»
Integragen CEO Bernard Courtieu said that his company is participating in SeqOIA solely as an industry partner. In this role, the firm will run the samples and report back data to the platform’s IT team. He noted that the SeqOIA team is closely in touch with Auragen in the south. «It is important that both platforms have a certain degree of homogeneity in their processes,» he said. «It would be inappropriate to have different choices of technology, IT, and so on.»
According to Courtieu, such harmonization also must remain true to the «values of the French healthcare system,» which guarantees equal access to healthcare. «It is important that there isn’t one platform here with its own setup and another that has different standards and processes,» he said. «So there is a very strong collaboration between Auragen and SeqOIA.»
While the new pilot platforms should enable French patients’ universal access to whole-genome sequencing, Courtieu noted that the country has accrued «significant experience in providing genomics to researchers and clinicians» in the past decade. «The 2025 plan was based on the understanding that genomics was ready to move to the clinic, and that large-scale genomics was something that was required or was soon to be required for at least cancer care and rare diseases and probably for other types of diseases,» he said.
«The goal was to be able to provide these services to patients wherever they are in France,» he said. «I think this is something that is fairly innovative and ambitious in terms of how it compares with other countries.»
Stoppa-Lyonnet also stressed that the French project was medical in nature, and not a research project. «It is a very important difference,» she said. «The idea is to introduce genomics into patient care.»
There are multiple patient-focused genomics projects underway in Europe at the moment, each of which has taken a different approach to introducing genomics into the healthcare system. Finland, for example, last year
announced plansto genotype 500,000 people as part of a five-year, €59 million project. Estonia also
set aside moneyto genotype 100,000 people this year as part of its personalized medicine project, and some disease risk is already being reported back to certain patients in pilot programs. Also, Denmark
recently established a National Genome Centerto provide a national sequencing infrastructure and to manage a centralized database.
Closer to France, Switzerland set aside CHF 40 million ($41 million) in 2016 to create a national infrastructure for sharing clinical data, including genomics data, throughout the country. And Genomics England, launched more than five years ago, recently announced the completion of 100,000 genomes related to cancer and rare diseases for patients within the country’s National Health Service, and is widely seen as a pioneer program in Europe.
The idea of data consolidation, standardization, and sharing is certainly core to PFMG 2025, too. As outlined in a
2016 reportpublished by Aviesan, the French National Alliance for Life Sciences and Health that is overseeing the project, the 2025 plan calls for the establishment of a so-called National Center for Intensive Calculation for processing and analyzing the data generated by the new sequencing platforms. The plan also calls for creating standardized, interoperable electronic patient medical records in France to support the analysis of genomic and clinical data.
«The idea is to build a center that can store all the data from all the sequencing that can be used later for research analysis, algorithms, and artificial intelligence, and also for the healthcare professionals who need to access information from patients,» said Ines Amado, deputy director at Aviesan. According to Amado, the new center is not yet operational, though it is being created.
She described it as a «physical center» that will be remotely accessible to researchers.
Amado noted that though all of the ongoing medical genomics projects in Europe are different, those involved in PFMG 2025 are in touch with colleagues in other countries. For example, the initiative has signed a memorandum of understanding with Genomics England to foster collaboration.
«Every country will have its own choices, but it helps to communicate because we can learn from each other,» Amado said.
Helse SørØst ledet i 2013-14 en nasjonal utredning fra helsevesenet om persontilpasset medisin som ga opphav til denne rapporten. Alle høringssvarene kan lastes ned her: innspillsrunde oppsummert. Da rapporten ble trykket ble anbefalingen om regionale sentre «ved en inkurie» endret til et nasjonalt senter, og Arbeiderpartiet fremmet for Stortinget et Dokument 8-forslag om å etablere dette umiddelbart. Da «uklarhetene» om anbefalingene ble kjent ble dette trukket. Du kan se stortingsdebatten om forslaget her.
På bakgrunn av den første utredningen ga Helsedepartementet Helsedirektoratet i oppdrag å utforme en strategi for hvordan metoder for bedre persontilpasning av helsetjenestene kan iverksettes. deres nasjonale strategi for persontilpasset medisin i helsetjenesten går inn for en beskjeden satsing, som førte til at HOD satte 8 Mkr til dette på statsbudsjettet for 2017. Av dette er 5 Mkr satt av til en nasjonal variantdatabase, formodentlig til den gode løsningen som allerede er etablert av NCGC ved OUS: 1000genomes.no. Her kan alle norske enheter som genererer NGS-data legge inn sine variantfrekvenser gjennom en lokal programvare som bare sender ut anonymiserte oversikter over frekvensene, og ikke identifiserbare kombinasjoner av varianter (halpotyper). Helsedirektoratet pekte spesielt på denne løsningen i sin rapport.
De øvrige midlene er satt av til et faglig nettverk, men RHFenes sider om satsingen er tatt bort. De har imidlertid publisert en Rapport om Nasjonalt nettverk av regionale fagråd innen persontilpasset medisin.
HDIRs rapport ble sendt på høring, og svaret fra HelseVest kan leses her. Det fra OUS har også mange gode poenger.
HDIR har også fått i oppdrag å planlegge en iverksettelse i helsevesenet, (men heller ikke på deres side ser jeg noe om iverksettelse).
I 2018 er det satt av ytterligere 19 Mkr.
Forskningsrådet har laget en Handlingsplan for forskning og innovasjon innenfor persontilpasset medisin, og har holdt en worskhop om næringsrettet innsats for å følge opp handlingsplanen og en rapport fra møtet. Det er mye god vilje, men ingen konkrete tiltak.
Samtidig som utviklingen i Norge er handlingslammet av ulike syn og manglende kompetanse i forvaltningen, ser vi hvordan svenskene og danskene er i full gang, og Storbritannia leder feltet.
Det å tilpasse både helseråd og medisinsk behandling til den enkelte pasient har alltid vært en integrert del av legens vurdering. Når dette begrepet nå har kommet i fokus er det derfor fordi mulighetene til å både diagnostisere sykdom mer presist, og vurdere tiltakene i forhold til hver enkelt pasients personlige egenskaper har økt så dramatiski de senere år. Dette gjelder særlig teknologier som analyserer ned til minste detalj oppbyggingen av genene og deres aktivitet i sykdomsprosessene, såkalt dypsekvensering, eller neste-generasjons-sekvensering (NGS).
Selv om mange teknologier, også innenfor NGS, kan brukes til mer presis diagnose, er fokus mes på analyse av den enkelte persons genvariasjon, som både kan bidra til sykdomsutvikling og påvirke om og hvordan behandlingen virker, og ved kreftsykdom, hvilke mutasjoner som er i svulsten, og hvordan disse påvirker sykdomsutviklingen og muligheten for behandling. I begge tilfeller dreier det seg da om analyse av selve arvestoffet, DNA, vanligvis i blod for analyse av det virkelig arvelige DNAet i «kimbanen», det som går fra foreldre til barn gjennom generasjoner, men som også muterer om enn i liten grad i hevrt individ, eller DNAet som bare arves gjennom kreftcellene i svulsten for kreftsykdom. I det siste tilfelle må man normalt sammenligne med variantene i pasientens blodprøve, for å skille mellom mutasjoner og varianter som er arvelige.
Det snakkes også om skreddersydd medisin, som i de fleste tilfeller er en misvisende betegnelse, vi snakker mer om å gå fra «one size fits all» til konfeksjon, enn å kunne tiklpasse spesifkt for hvert individ. En bedre betegnelse som brukes ofte er presisjonsmedisn, men også den blir ikke helt dekkende.
