Over the last twenty years, advances in next-generation sequencing (NGS) technologies have enabled the efficient and cost-effective sequencing of human genomes. A particularly impactful application of these technologies is in the study of health and disease. Our deeper understanding of human physiology and pathophysiology at the genetic level is facilitating a personalized and tailored approach to healthcare that considers the individual and their unique constitution, rather than stratifying patients into large, population-size groups.
In the UK, Genomics England is pioneering a "lasting legacy" for patients by introducing genomic sequencing into the wider healthcare system. Initially, the aim of Genomics England was to sequence 100,000 human genomes through The 100,000 Genome Project, funded by the National Institutes for Health Research and NHS England. In 2018, the project met this goal, and announced that it would be extended to sequence five million whole genomes over a five-year period.
Technology Networks spoke with Dr Richard Scott, clinical director at Genomics England, to learn more about the utility of NGS in modern medicine, from prevention and diagnosis to tailoring treatment. Scott also discusses the wide-range of applications of genomics in understanding diseases, particularly pathogens such as SARS-CoV-2, and emphasizes the importance of having open conversations with the public about the utility of genomic data.
Molly Campbell (MC): To begin, please can you discuss why obtaining and using genetic data in a clinical context is a priority for the UK?
Richard Scott (RS): The last 10 years have been really exciting, as we have seen genetic data transition from being something that is useful in a small number of contexts with highly targeted tests, towards being a central part of mainstream healthcare settings. From the UK's perspective, what has been really crucial is our ability to invest in the infrastructure that lets us harness genomic data. This has involved embedding new technologies, such as whole genome sequencing (WGS), into healthcare settings and assessing how we do this and embed the technology in day-to-day clinical practises.
Currently, genetic data is used to guide patient healthcare in two main settings. The first is cancer, where genetic data is used to understand what type of cancer a patient has, how to best care for them and how to tailor their medication. The second is in treating rare diseases, such as Mendelian diseases that follow a set pattern of inheritance. Whilst individually these diseases are fortunately rare, collectively they are quite common – one in 17 of us will suffer from a disease that it classed as rare. WGS is useful in diagnosing these conditions and working to identify the genetic cause and the best plan of action for treating the patient.
And it’s not that far off before we can see a situation where we will routinely be using genetic data to personalize the doses of medicine that patients require depending on, for example, how quickly their body metabolizes a particular drug. Tailoring pharmacology in this way is known as pharmacogenomics.
MC: Can you talk to us about the history of the 100,000 Genomes Project and what it has achieved thus far?
RS: A little under 10 years ago in the UK, the government and the scientific community recognized that there had been a big change in terms of the technology to sequence genes and the know-how. Next-generation sequencing (NGS) had emerged and was becoming a much more mature technology. Sequencing the first human genome in the Human Genome Project cost billions of pounds, and suddenly we found ourselves in a position where a £1000 genome was on the horizon.
We were at the tipping point where you could start to use WGS to guide healthcare. As a result, the UK government set the vision to deliver a project known as The 100,000 Genomes Project, which would explore the use of WGS in healthcare to benefit patients in the NHS. The project would also be used to explore how we build an infrastructure for the implementation of WGS in wider healthcare settings in the future.
Genomics England was set up by the UK government in 2013 to deliver the project in partnership with the NHS. The project focused on the two areas that could be seen to immediately benefit from WGS: rare diseases and cancer.
The program has recruited patients through the NHS community, who have been critical partners in delivering the project. Now, through the project, more than 10,000 families have been diagnosed with a rare disease. We made a diagnosis in approximately one quarter of the families that were recruited to the program.
In cancer, the project has provided us with an evidence base that the NHS can access and commission to say that WGS is ready for primetime use, not just in a research program. That is where we are today.
The amount of data generated by WGS is quite large and you really need a system that can process the data well to achieve that vision. We are working with the NHS to launch the first WGS service to be delivered in a national healthcare system. We are at the final stages of testing the system before it goes live. This is the biggest legacy of The 10,000 Genomes Project.
MC: Is whole genome sequencing the only genomics tool that can be adopted in personalized medicine approaches?
RS: WGS is just part of the equation. NHS England, the commissioners of genomic healthcare in England, have constructed their NHS Genomic Test Directory that sets out their expectations for the use of different genomic technologies, with WGS at one end and highly targeted tests at the other end. There are a wide range of technologies that can be useful in different settings, and their application in addressing specific clinical questions changes over time, depending on certain factors. For example, the declining cost associated with WGS is a really big factor that has enabled its clinical utility.
Also, the scope of what the technology and the bioinformatics data processing systems are able to detect reliably has also improved. But there are genetic variations next generation sequencing cannot detect, for example changes in DNA methylation, and so you need different tests to look for these. It is a matter of working out which test is right for the scenario, and WGS is an increasing part of that, but it is not the whole picture.
MC: What other disease areas have we seen benefiting from genomic sequencing?
RS: Genomics and WGS in infectious diseases is really important. Part of the 100,000 Genomes Project was a program looking at the sequencing of tuberculosis (TB) genomes, which are much smaller and therefore considerably simpler to sequence compared to human genomes. The project was looking to understand resistance to certain medications, as this can be an issue in TB treatment. In addition, we have seen that sequencing of the coronavirus is absolutely crucial, so infectious disease is a really big area for the use of genomic sequencing. Typically, this focuses on sequencing the virus or the pathogen and understanding the interplay between the pathogen and the individual.
Another area is pharmacogenomics; selecting the right drug or dose of a drug for an individual based on the characteristics of their genome. A new service recently launched by the NHS known as DPYD testing which helps us to understand the dosing of particular chemotherapy drugs, like Fluorouracil. Pharmacogenomics will become very mainstream over time, but at the moment, we are at the beginning of the story.
Another broad area for the application of genomics is in disease prevention, rather than diagnosis or tailoring of a specific treatment. Genomics is not mainstream here just yet, but it is an area where we expect its use to grow.
MC: Scientific research is pointing towards the value in utilizing proteomics and metabolomics, in addition to genomics, for advancing personalized medicine. What are your thoughts on this, and how do you think it will impact the future of medicine?
RS: There is a real potential for using multiple strands of data alongside each other, both for discovery – helping us to understand new things about diseases and how their affect the body – but also in terms of live health care.
A real-life example of this interplay can be seen in COVID-19 research. We have been working in partnership with a program called GenOMICC at the University of Edinburgh where we have been seeking to understand the clinical variability in COVID-19 cases. We can see genomic influences on the risk of needing critical care in COVID-19 patients and in how their immune system is behaving. Looking at this data alongside other omics information, such as the expression of different protein levels, helps us to understand the disease process better. It is also helping us to identify potential drug targets that might be used in trials such as the RECOVERY trial, and to try and reduce the risk of people getting sick with COVID-19.
MC: What ethical considerations must be made when implementing genomic sequencing as part of routine care?
RS: I think one of the most important things is to be able to have conversations with patients and the public health about what people are comfortable with. This is not data that is owned by research studies, but it is collected from participants who chose to enter research programs, and so how it is used should be the choice of that individual.
In 2019 there was a piece of work that we supported on request of the Chief Medical Officer, known as "Public Dialogue on Genomics", where we worked with the NHS and the public to address some of the ethical issues associated with genomic data and to gauge an understanding of the public's attitudes. A clear message we received from this dialogue was that people's desire is for their data to be used for altruistic purposes. There were also some very clear lines about what the public did not want their data to be used for. Being able to have those conversations puts you in a really strong position. This has been central to what we have been doing at Genomics England, and to the successes that we have had.
We also, through the governance of our structure, have a participants panel that we can talk to. They are representatives of all the participants whose data we have been working with and have been responsible for. This panel has been crucial in driving our direction and for providing confidence in our next steps. Often as a doctor I am anxious about making assumptions about what people want, and so my tendency is to be more cautious. But what the participants tell you is that they do want their data to be used in a certain way, or made available to researchers, and we need to listen to that.
Members of our participants panel also sit on our data access committee – and other similar committees – so they are driving the decisions on how data is used. I think that is really crucial, both to maximize the benefits of programs, but also for maintaining trust.
MC: Last year the UK government published its National Genomic Strategy, Genome UK. Can you tell us more about Genome UK and how WGS will be embedded in routine healthcare?
RS: What I really like about the National Genomic Strategy is that it sets out the different components of our plan to integrate genomics in different areas, from diagnosis and personalized medicine, through to prevention and research. The strategy spans the whole ecosystem of medicine and helps to plan what the different components of the UK efforts are, for example the UK BioBank, which is focusing on research in preventions – understanding disease risk.
It it also considers the important cross-cutting themes that we need to get right, such as engagement and dialogue with the public and participants in the program and ensuring that the workforce has the appropriate skills so that we have correct infrastructure to deliver the program.
What is really encouraging is how well it has been received in the community. We have a really good history in the UK and recognition for our historical know-how and scientific strengths in this area, and we have been lucky in terms of government and NHS investment. But we also have a strategy here that really makes sense going forward, and strong indications of the ongoing aspiration for the UK to be a real global leader in this space.
Richard Scott was speaking to Molly Campbell, Science Writer for Technology Networks.