Behind the Genes

In this explainer episode, we’ve asked Dr Emily Perry, research engagement manager at Genomics England, to explain what the Genomics England Research Environment is. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. You can listen to the previous episodes mentioned in this podcast How has a groundbreaking genomic discovery impacted thousands worldwide? What is the National Genomic Research Library If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What is the Genomics England Research Environment? My name is Florence Cornish and I'm here with Emily Perry, Research Engagement Manager at Genomics England, to find out more. So Emily, before we dive into the Research Environment, let's set some context. Could you explain what Genomics England is aiming to do as an organisation? Emily: So, Genomics England provides genome sequencing in a healthcare setting for the National Health Service in England. As we sequence genomes for healthcare, the benefit is that we can also put that genomic and clinical data out for research in a controlled manner, and then that can also feed back into healthcare as well. So, it's really, this kind of cyclical process that Genomics England is responsible for. Florence: And so, what do we mean when we say Research Environment? Emily: So, the Research Environment is how our researchers can get access to that clinical and genomic data that we get through healthcare. So, it's a controlled environment, it's completely locked down, so it's kind of like a computer inside a computer. And in there, the researchers can access all of the data that we have and also a lot of tools for working with it in order to do their research. We refer to the data as the National Genomics Research Library, or the NGRL. The NGRL data is provided inside the Research Environment Florence:  So you mentioned the National Genomic Research Library. If any listeners want to learn more about this, you can check out our previous Genomics 101 podcast: What is the National Genomic Research Library? And so Emily, could you talk about what kind of data is stored in this library? Emily: So the library is made up of both genomic data and clinical data, which the researchers use alongside each other. The genomic data includes what we call alignments, which is where we match the reads from sequencing onto a reference sequence, and variants, which is where we identify where those alignments differ from the reference sequence, and this is what we are looking for in genomic research. The clinical data includes the data that was taken from our participants at recruitment, so details of the rare disease, the cancer, that they have, but also medical history data. So, we work with the NHS and we're able to get full medical history for our participants as well. This is all fully anonymised, so there's no names, there's no dates of birth, there's no NHS numbers. It's just these identifiers which are used only inside the Research Environment and have no link to the outside world. Florence: And so how is this clinical and genomic data secured? Emily: So, as I said there's no names, there's no NHS numbers, there's no dates of birth.  And we have very strict criteria for how people can use the data. So researchers, in order to get access to the Research Environment, they have to be a member of a registered institution, they have to submit a project proposal for what it is that they want to study with the data. There's also restrictions on how they can get the data out, so they do all their research inside, there's no way that they can do things like copy and paste stuff out or move files. The only way that they can get data out of the Research Environment is going through a process called Airlock, which is where they submit the files that they want to export to our committee, who then analyse it, check that it's in accordance with our rules and it protects our participants' safety and that only then would they allow them to export it. Florence: Who has access to the Research Environment? Emily: We have researchers working with the Research Environment all over the world. There's 2 kind of major groups. One of them is academia, so this will be researchers working in universities and academic institutions. The other side of it would is industry - so this will be biotech, startups, pharma companies, things like that. Florence: And finally, can you tell us about some of the discoveries that have been made using this data? Emily: There's lots of really cool things that have come out of the Research Environment.  A recent story that came out of the Research Environment was the ReNU syndrome, it was initially just one family that they identified this in, and they were able to extend this discovery across and identify huge numbers of individuals who had this same disorder because they had their genomes within the Research Environment. Florence: You can hear more about this research in our previous Behind the Genes podcast: How has a groundbreaking genomic discovery impacted thousands worldwide? So, we'll wrap up there. Thank you so much, Emily, for sharing more about what we mean by the Genomics England Research Environment. If you'd like to hear more explain episodes like this, you can find them on our website, at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.  

In this episode, we step inside the NHS to explore how the Generation Study is brought to life - from posters in waiting rooms to midwife training. We follow the journey of parents joining the study at the very start of their baby’s life, and hear from those making it happen on the ground.  Our guests reflect on the teamwork between families and hospitals, the importance of informed consent, and the powerful insights this study could unlock for the future of care and research.  Our host Jenna Cusworth-Bolger, Senior Service Designer at Genomics England, is joined by:  Tracie Miles, Associate Director of Nursing and Midwifery at the South West Genomic Medicine Service Alliance, and Co-Investigator for the Generation Study at St Michael’s Hospital in Bristol Rachel Peck, parent participant in the Generation Study and mum to Amber If you enjoyed today’s conversation, please like and share wherever you listen to your podcasts.  For more on the Generation Study, explore:  Podcast: How has design research shaped the Generation Study  Podcast: What can we learn from the Generation Study  Podcast: What do parents want to know about the Generation Study  Blog: Genomics 101 - What is the Generation Study  Generation Study official website   “I think from a parent’s point of view I guess that's the hardest thing to consent for, in terms of you having to make a decision on behalf of your unborn child. But I think why we thought that was worthwhile was that could potentially benefit Amber personally herself, or if not, there's a potential it could benefit other children.” You can download the transcript, or read it below. Jenna: Hi, and welcome to Behind the Genes.   Rachel: I think if whole genome sequencing can help families get answers earlier, then from a parent perspective I think anything that reduces a long and potentially stressful journey to a diagnosis is really valuable. If a disease is picked up earlier and treatment can start sooner, then that could make a real difference to a child or even Amber’s health and development. Jenna: My name is Jenna Cusworth-Bolger and today I have the great pleasure to be your host. I’m a senior service designer at Genomics England specifically working with the hospitals involved in delivering the Generation Study. In March 2023 we started with our very first hospital, St. Michael’s in Bristol. I am today joined by Tracie Miles who I had the utter pleasure of working closely with when they were setting up. And we also have Rachel Peck, one of the mums who joined the study in Bristol. Regular listeners to this podcast may already be familiar with the Generation Study but for those who are not, the Generation Study is running in England and aims to sequence the genomes of 100,000 newborn babies from a cord blood sample taken at birth. The families consented to take part will have their babies screened for over 200 rare genetic conditions most of which are not normally tested for at birth. We expect only 1% of these babies to receive a condition suspected result, but for those 1,000 families that result could be utterly life changing as it could mean early treatment or support for that condition. Would you like to introduce yourselves and tell us what it means to you to have been that first hospital open in this landmark study. Tracie, I’ll come to you first.  Tracie: Hi Jenna, lovely to be with you all this morning. And for those who are listening it is early in the morning, we get up early in the morning because we never know when these babies are going to be born on the Generation Study and we have to be ready for them. So, my name is Tracie, I am the Co-Investigator with the wonderful Andrew Mumford, and we work together with a huge team bringing this study to life in Bristol. I am also the Associate Director of Nursing and Midwifery at the South West Genomic Medicine Service Alliance. Jenna: Thanks Tracie. We’re also joined today by Rachel. Would you like to introduce yourself and your baby, and tell me when you found out about the Generation Study?  Rachel: Hi, thank you for inviting me. My name’s Rachel, I’m based in Bristol. My baby is Amber; she was born four months ago in St. Michael’s hospital in Bristol. I first heard about the Generation Study when I was going to one of my antenatal appointments and saw some of the posters in the waiting room. Amber is napping at the moment, so hopefully she’ll stay asleep for long enough for the recording. Jenna: Well done, that's the perfect mum skill to get a baby to nap whilst you’re busy doing something online. So, Rachel, you said you heard about the study from a poster. When you first saw that poster, what were your initial thoughts? Rachel: I thought it was really interesting, I haven’t come across anything like that before and I thought the ability to screen my unborn baby at the time’s whole genome sounded really appealing.  Jenna: Fantastic. So, what happened after the poster?  Rachel: If I remember correctly, I scanned the QR code on the poster which took me to the website. I filled out a few simple questions online and then I was contacted by one of the research team where I arranged a formal consent conversation. That was done by Zoom I think in the evening because I’ve already got a toddler at home so post bedtime works best for me. So, we had about a forty-minute conversation on the phone where I could ask all the questions that I needed to ask and if I was happy which I was. I then gave my consent and then I believe my maternity records were kind of highlighted to say that I signed up for the Generation Study and that when my baby was born then a sample was going to be taken, and I would be given the results in due course. Jenna: And did all that go smoothly, that you’re aware of? Rachel: Yeah, as far as I’m aware. It was genuinely really simple to do. After that initial consultation where I signed the consent form there wasn’t any follow-up appointments so the next thing I knew, I think it was just chance, but one of the research nurses actually came down to see me on the day which was really nice. Just to say, ‘Oh, just to let you know that the team are aware.’ And then, other than that, the next thing I knew was getting the results through by post. Jenna: Sure. So, behind the scenes your baby’s blood was collected from the umbilical cord, that would have been registered, packaged, sent off and went on a whole journey for you to ultimately get your result. It all sounds very simple, but I think we’re going to dig into a lot of the mechanisms that kind of went behind the scenes to make something that seems simple come to life. Tracie, we met in the summer of 2023 I believe. I came to St. Michaels with a suitcase full of our materials which we had started to bring to life, including that poster. We’ve sat together and we were trying to figure out exactly how this was going to come to life in our very first hospital and how, what Rachel described, was actually going to become real. Tracie, can you tell me what you remember about those conversations and the thinking that you did as a team ahead of getting that green light to go ahead and start recruiting?  Tracie: Listeners, just to let you know that Rachel hasn’t been primed to say that it was a seamless journey from delivery to getting results. I’m delighted to hear that it was. And I think the reason that we’ve achieved that in Bristol and across England now with the other teams that Jenna and the team have helped roll out, is teamwork. And part of our team is our mum, in this case Rachel. If you hear me or Jenna describing our mums as "Mia", that's the name, the significant name or the identifier we give for our participant. So, yeah, Jenna, I think the thing was it was about those first conversations. It was about teamwork and who shall we involve? We involved everybody didn’t we, Jenna? So, I know that the team, by the time they came to us they'd already been planning for two years. So, in fact what came to us in Bristol was a wealth of work and information, and two years of behind the scenes of the team working. We involved every midwife. Now a midwife is a cover all term.  We involve community midwives, research midwives, antenatal midwives, post-natal midwives. They all do different things for the mum pathway. Not forgetting dad as well, he is involved in all of this and Rachel I’m sure will testify later to the fact that when she was offered the consent, her partner was offered to come along too. UHBW, that’s United Hospital Bristol and Western, that our maternity hospital as part of, have got a fantastic R&D department and they were on straightaway with the rule book checking that we knew what we were doing. So, for those of you that aren’t in the medical world, that's making sure we’ve got the right governance, that we’re doing things by the rule book. Andrew went out and spoke to lots of different clinicians that would be involved in the pathway after the results were back, for those babies where we found a condition suspected. So, essentially Jenna, I think the list that was fairly long, grew longer and longer. Jenna: I think that was something that I was really struck by when I came back and visited you repeatedly after that. You were particularly good at getting some of those staff members that you might not even think about involved in the study, like the receptionist on your sonography department who you had recruited to make sure that they gave out the leaflet and the participant information sheet to all the mums coming in for their twenty-week scans etc. All that thinking was really valuable and something that I’ve passed on and taken out on my trips to other hospitals along the way. We heard from Rachel that she heard about this study from the poster. Now that you’ve been going for just over a year, what are all the different ways that people hear about the study, is it just the poster? Tracie: No, it’s not just the poster. So, essenti

In this explainer episode, we’ve asked Dr Nour Elkhateeb, clinical fellow at Genomics England and clinical geneticist for the NHS, to explain the role of a clinical geneticist. The previous episode mentioned in the conversation is linked below. What is the diagnostic odyssey? You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What is a clinical geneticist? My name is Florence Cornish and I'm here with Nour Elkhateeb, clinical geneticist for the NHS and fellow at Genomics England, to find out more. So, Nour, before we dive into talking about clinical geneticists, could you explain what we mean by the term genetics? Nour: Hi Florence, so at its heart, genetics is the study of our genes and how they are passed down through families. Think of your genome as a huge, incredibly detailed instruction manual for building and running your body. This manual is written in a specific language, DNA, which is made up of millions of letters arranged in a specific order.  And here is the interesting part, we all have tiny differences in our genetic spelling, which is what makes each of us unique.  But sometimes a change in the instructions, a spelling mistake in a critical place, can affect health. Genetics is all about learning to read that manual, understand how changes in it can cause disease, how it's passed down through families and finding ways to help.   Florence: And so, what kind of thing does a geneticist actually do? Nour: Well, the term geneticist can cover a few different roles, which often work together. Crudely speaking, you can think of two main types, laboratory geneticists and clinical geneticists.   Laboratory geneticists are the incredible scientists who work behind the scenes. When we send a blood sample for genomic sequencing, they are the ones who use amazing technology to read the billions of letters in that person's instruction manual. The job is to find the one tiny spelling mistake among those billions of letters that might be causing a health problem.  Clinical geneticists like me are medical doctors specialised in the field of genetics, and we work face-to-face with patients and families in a hospital or a clinic setting. You can think of us as the bridge between the incredibly complex science of the genomics lab and the real-life health journey of the person in front of them. We diagnose, manage and provide support for individuals and families who are affected by or at risk of genetic conditions. And we translate that complex genetic information into meaningful information for the patient, the family and the other doctors as well.  Florence: So, let's talk a little bit more about clinical geneticists. What stage of someone's genomics journey are they likely to see you? What are some typical reasons they might get referred, for example?  Nour: That's a really good question. So, people actually can be seen by clinical geneticists at almost any stage of life, and for many different reasons. Let me give you some examples.  We see a lot of babies and children. A family may be referred to us if their baby is born with health problems that do not have a clear cause, or if a child is not developing as expected. And sometimes families may have been searching for answers for years, or what we call a diagnostic odyssey, but no one has been able to find a single unifying diagnosis to explain their challenges. And our job is to see if there is a genetic explanation that can connect all the dots.  Florence: You touched there on the diagnostic odyssey, and I know we don't have time to dive into that right now, but if listeners want to learn more about this, then they can check out our previous Genomics 101 podcast: What is the Diagnostic Odyssey? So, Nour, we know that you see children and families in their genomics journeys. Do you see adults as well?  Nour: Yes, indeed. We also see many adults who develop certain health conditions, such as cancer or certain types of heart disease, and their clinicians suspect they might be having an underlying inherited genetic cause, or it could be actually someone who is healthy themselves, but have a family history of a particular condition, and want to understand their own risk or the risk for their children and other family members. A classic example is in cancer genetics. A woman with breast cancer at a young age, or who has several family members who have also had it, she would be investigated to see if she carries a gene change that increases the risk of breast cancer and other cancers, and finding that actually would be critical for the treatment choices, and it has huge implications for her relatives.  Also, a major part of our work is in the prenatal setting, so we might see a couple during a pregnancy if the antenatal ultrasound scan, for example, shows that the baby has abnormalities. And the obstetrician might refer them to us to investigate if they have an underlying genetic reason for that. And this can help the couple and the medical team prepare for any challenges after birth and also make informed decisions about the pregnancy.   And clinical genetics is unique in that we don't see just individual patients, we often work with entire families, and if there is an inherited condition in the family, it's not unusual for several relatives across different generations to be seen by our team.  This family-wide approach helps us piece together the inheritance pattern and offer the right tests to the right people, and also ensure that everyone who might benefit from information or screening has the opportunity to access that.  Florence: So if someone has a suspected genetic condition, will they always come to you first?  Nour: Actually no, the way people come to us is changing. It used to be that you would always see clinical geneticists first, but now with genetic testing becoming more common, other clinicians like a cardiologist, a neurologist, or a paediatrician, might order a genetic test themselves.   But these tests can produce a huge amount of data, and the results are not always a simple yes or no. Sometimes the lab finds something called a variant of uncertain significance, which means a gene change that we are not certain whether it is the cause of health problems or not. And in these cases, a specialist will refer the patient to us to help put the uncertain result into the context of the patient's specific health problems, and family history, and to help also work out what it really means for them and their family.  Florence: So, you mentioned a couple of other healthcare professionals there, paediatricians and neurologists for example. Are there any other roles that you work closely with as a clinical geneticist?  Nour: Well, genetics is never a one-person job, and it's rather like a team sport, so we never work in isolation. We work in what we call a multidisciplinary team,  where clinical geneticists, genetic counsellors, genomic practitioners, scientists and other specialists, all bring our knowledge and expertise together. We also work directly with other specialists across the hospital and the NHS. Let's say if it's a genetic heart condition, a cardiologist would be a key part of this multidisciplinary team for the patient. And this 360-degree view ensures that we are giving the best possible holistic care.   Florence: And finally, before we wrap up, I'm sure lots of our listeners may have heard or even come across genetic counsellors. Could you explain how this role is different from a clinical geneticist?  Nour: So, our role as a clinical geneticist is distinct from that of a genetic counsellor, but we work side by side. Clinical geneticists, as the medical doctors on the team, we're often focused on the diagnosis, and we will perform a physical examination of the patient, looking for subtle clues. We will review their medical history, and piece together the whole medical puzzle. And based on that, we decide which genetic test is the most appropriate, and we'll have the best chance of finding an answer. A genetic counsellor is a healthcare professional with highly specialised training in both genetics and counselling. They are communication experts, they spend time helping families understand results, process the information, and think through what it means for them and their relatives. They are incredibly skilled at explaining complex genetic concepts in a way that is easy to understand, and also at providing support. They help families navigate the emotional impact of what can be life-changing news, and also discuss the implications for the wider family. And genetic counsellors are not only there after the diagnosis is made, they can also play an active role in the diagnostic process.  So in many situations, they are the ones taking the detailed family history, recognising patterns that suggest a genetic condition, and arrange the most appropriate genetic tests. They work closely with laboratory scientists and clinical geneticists to interpret the results and guide the next steps for the patient.  And a family will often see both of us as our roles complement each other.  Florence: So, we'll finish there. Thank you so much, Nour, for sharing what you do as a clinical geneticist.   If you'd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk, or wherever you get your podcasts. Thank you for listening. 

In this episode of Behind the Genes, we explore how Artificial Intelligence (AI) is being applied in genomics through cross-sector collaborations. Genomics England and InstaDeep are working together on AI and machine learning-related projects to accelerate cancer research and drive more personalised healthcare. Alongside these scientific advances, our guests also discuss the ethical, societal and policy challenges associated with the use of AI in genomics, including data privacy and genomic discrimination. Our guests ask what responsible deployment of AI in healthcare should look like and how the UK can lead by example. Our host, Francisco Azuaje, Director of Bioinformatics Genomics England is joined by Dr Rich Scott, Chief Executive Officer at Genomics England Karim Beguir - Chief Executive Officer at InstaDeep Harry Farmer – Senior Researcher at Ada Lovelace Institute If you enjoyed today’s conversation, please like and share wherever you listen to your podcasts. And for more on AI in genomics, tune in to our earlier episode: Can Artificial Intelligence Accelerate the Impact of Genomics? "In terms of what AI’s actually doing and what it’s bringing, it’s really just making possible things that we’ve been trying to do in genomics for some time, making these things easier and cheaper and in some cases viable. So really it’s best to see it as an accelerant for genomic science; it doesn’t present any brand-new ethical problems, instead what it’s doing is taking some fairly old ethical challenges and making these things far more urgent."   You can download the transcript, or read it below.   Francisco: Welcome to Behind the Genes. [Music plays] Rich: The key is to deliver what we see at the heart of our mission which is bringing the potential of genomic healthcare to everyone.  We can only do that by working in partnership.  We bring our expertise and those unique capabilities.  It’s about finding it in different ways, in different collaborations, that multiplier effect, and it’s really exciting.  And I think the phase we’re in at the moment in terms of the use of AI in genomics is we’re still really early in that learning curve. [Music plays] Francisco: My name is Francisco Azuaje, and I am Director of Bioinformatics at Genomics England.  On today’s episode I am joined by Karim Beguir, CEO of InstaDeep, a pioneering AI company, Harry Farmer, Senior Researcher at the Ada Lovelace Institute, and Rich Scott, CEO of Genomics England.  Today we will explore how Genomics England is collaborating with InstaDeep to harness the power of AI in genomic research.  We will also dive into the critical role of ethical considerations in the development and application of AI technologies for healthcare.  If you’ve enjoyed today’s episode, please like, share on wherever you listen to your podcasts. [Music plays] Let’s meet our guests. Karim: Hi Francisco, it’s a pleasure to be here.  I am the Co-Founder and CEO of InstaDeep and the AI arm of BioNTech Group, and I’m also an AI Researcher. Harry: I’m Harry Farmer, I’m a Senior Researcher at the Ada Lovelace Institute, which is a think-tank that works on the ethical and the societal implications of AI, data and other emerging digital technologies, and it’s a pleasure to be here. Rich: Hi, it’s great to be here with such a great panel.  I’m Rich Scott, I’m the CEO of Genomics England. Francisco: Thank you all for joining us.  I am excited to explore this intersection of AI and genomics with all of you.  To our listeners, if you wish to hear more about AI in genomics, listen to our previous podcast episode, ‘Can Artificial Intelligence Accelerate the Impact of Genomics’, which is linked in this podcast description. Let’s set the stage with what is happening right now, Rich, there have been lots of exciting advances in AI and biomedical research but in genomics it’s far more than just hype, can you walk us through some examples of how AI is actually impacting genomic healthcare research? Rich: Yeah, so, as you say, Francisco, it is a lot more than hype and it’s really exciting.  I’d also say that we’re just at the beginning of a real wave of change that’s coming.  So while AI is already happening today and driving our thinking, really we’re at the beginning of a process.  So when you think about how genomics could impact healthcare and people’s health in general, what we’re thinking about is genomics potentially playing a routine part in up to half of all healthcare encounters, we think, based on the sorts of differences it could make in different parts of our lives and our health journey.  There are so many different areas where AI, we expect, will help us on that journey.  So thinking about, for example, how we speed up the interpretation of genetic information through to its use and the simple presentation of how to use that in life, in routine healthcare, through to discovery of new biomarkers or classification that might help us identify the best treatment for people.  Where it’s making a difference already today is actually all of those different points.  So, for example, there’s some really exciting work we’re doing jointly with Karim and team looking at how we might use classification of the DNA sequence of tumours to help identify what type of tumour - a tumour that we don’t know where it’s come from, so what we call a ‘cancer of unknown primary’ - to help in that classification process.  We’re also working with various different people who are interested in classification for treatment and trials, but there’s also lots in between recognising patterns of genomic data together with other complex data.  So we’ve been doing a lot of work bringing image data together with genomic data and other health data so that you can begin to recognise patterns that we couldn’t even dream of.  Doing that hand in hand with thinking about what patients and participants want and expect, how their data is used and how their information is held, bringing it all together and understanding how this works, the evidence that we need before we can decide that a particular approach is one that policymakers, people in healthcare want to use, is all part of the conversation. Francisco: Thank you, Rich, for speaking of cutting-edge AI applications and InstaDeep.  Karim, could you give us a glimpse into your work and particularly how your technologies are tackling some of the biggest challenges in genomic research? Karim: Absolutely, and I think what’s exciting is we’ve heard from Rich and, you know, this is like the genomics expertise angle of things and I come from the AI world and so do most of the InstaDeep team.  And really what’s fascinating is this intersection that is being extremely productive at the moment where technologies that have been developed for like multiple AI applications turn out to be extremely useful in understanding genomic sequences.  This is a little bit, our journey, Francisco.  Back in 2021/2022 we started working on the very intriguing question at the time of could we actually understand better genomic sequences with the emerging technologies of NLP, natural language processing.  And you have to put this in context, this was before even the word ‘generative AI’ was coined, this was before ChatGPT, but we had sort of like an intuition that there was a lot of value in deploying this technology.  And so my team, sort of like a team of passionate experts in research and engineering of AI, we tackled this problem and started working on it and the result of this work was our nucleotide transformer model which we have open sourced today; it’s one of the most downloaded, most popular models in genomics.  And what’s interesting is we observed that simply using the technologies of what we call ‘self-supervised learning’ or ‘unsupervised learning’ could actually help us unlock a lot of patterns. As we know, most of genomics information is poorly understood and this is a way actually, with using the AI tool, to get some sense of the structure that’s there. So how do we do this?  We basically mask a few aspects of the sequence and we ask the system to figure them out.  And so this is exactly how you teach a system to learn English, you know, you are teaching it to understand the language of genomics, and, incredibly, this approach when done at scale - and we train a lot on the NVIDIA Cambridge-1 supercomputer – allows you to have results and performances that are matching multiple specialised models.  So until then genomics and use of machine learning for genomics was for a particular task, I would have developed a specific model using mostly supervised learning, which is, I am showing you a few examples, and then channelled these examples and tried to match that, and so essentially you had one model per task.  What’s really revolutionary in this new paradigm of AI is that you have a single model trained at very largescale, the AI starts to understand the patterns, and this means that very concretely we can work with our partners to uncover fascinating relationships that were previously poorly understood.  And so there is a wealth of potential that we are exploring together and it’s a very exciting time. Francisco: What you’re describing really highlights both the potential and the opportunities but also the responsibility we have with these powerful tools, its power, and this brings up some important ethical considerations.  And we have Harry…  Harry, we have talked about ethics frameworks in research for decades but AI seems to be rewriting the rulebook.  For your work at the Ada Lovelace Institute what makes AI fundamentally different from previous technologies when it comes to ethical considerations and how does this reshape our approach to ensuring these powerful tools benefit society as a whole? Harry: So I think when you are considering these sorts of ethical questions and these sorts of ethical challenges posed by AI and genomics it really depends on the sort of deployment tha

In this episode of Behind the Genes, we explore the hopes, concerns and complex questions raised by the idea of a lifetime genome — a single genomic record used across a person’s life to guide healthcare decisions. Drawing on conversations from Genomics England’s Public Standing Group on the lifetime genome, our guests explore what it might mean for individuals, families and society to have their genome stored from birth, and how it could transform healthcare. The discussion reflects on the potential for earlier diagnoses, better treatments and long-term prevention, alongside pressing ethical concerns such as data security, consent, and the impact on family dynamics. Participants share their views and discuss the future role of genomic data in medicine, with insights into how trust, equity and public dialogue must shape this evolving field. Our host for this episode, Dr Harriet Etheredge, is joined by Suzalee Blair-Gordon and Gordon Bedford, two members of the Genomics England’s Public Standing Group on the lifetime genome, and Suzannah Kinsella, Senior Associate at Hopkins Van Mil, a social sciences research agency that helped to facilitate this work. Together, they consider the broader societal implications of lifetime genomic data, and how public involvement can help guide policy and practice in the UK and beyond. This conversation is part of our ongoing work through the Generation Study, exploring how genomics can be used responsibly and meaningfully from birth onwards. You can listen to some of our Generation Study episodes by following the links below. What can we learn from the Generation Study? How has design research shaped the Generation Study? What do parents want to know about the Generation Study?   "This isn’t just a science project, it’s about designing a future where everyone feels included and protected. We need more voices, parents, young people, underrepresented communities, to keep shaping it in the right direction."   You can download the transcript, or read it below. Harriet: Welcome to Behind the Genes. Suzalee: I have come to terms with the thought that life is unpredictable and I have already begun to accept any health condition that comes my way. Believe you me, I have been through the stage of denial, and yes, I have frozen upon hearing health diagnoses in the past but now I believe that I am a bit wiser to accept the things that I cannot change and to prepare to face the symptoms of whatever illness I am to be dealt with or to be dealt to me. If the analysis of my genome can help me to prepare, then yes, I am going to welcome this programme with open arms.  Harriet: My name is Harriet Etheredge, and I am the Ethics Lead on the Newborn Genomes Programme here at Genomic England. On today’s episode I’m joined by 3 really special guests, Suzalee Blair and Gordon Bedford, who are members of Genomics England’s Public Standing Group on Lifetime Genomes, and Suzannah Kinsella, Senior Associate at Hopkins Van Mil, a social sciences research agency that has helped us to facilitate this work.  Today we’ll be discussing the concept of the lifetime genome. What do we mean when we say, ‘lifetime genome’? How can we realise the promise of the lifetime genome to benefit people’s healthcare whilst at the same time really appreciating and understanding the very real risks associated? How do we collectively navigate ethical issues emerging at this genomic frontier? If you enjoy today’s episode, we would really love your support. Please share, like and give us a 5-star rating wherever you listen to your podcasts. And if there’s a guest that you’d love to hear on a future episode of Behind the Genes, please contact us on podcast@genomicsengland.co.uk. Let’s get on with the show. I’ll start off by asking our guests to please introduce yourselves.  Suzalee, over to you.  Suzalee: Thanks, Harriet. So I am a proud mum of two kids, teacher of computing at one of the best academic trusts in the UK, and I am also a sickler, and for those who don’t know what that means, I am living with sickle cell disease.  Harriet: Thank you so much, Suzalee. Gordon, over to you.  Gordon: I’m Gordon Bedford, I’m a pharmacist based in The Midlands. I’ve worked in hospital and community pharmacy. I have a genetic condition, which I won’t disclose on the podcast but that was my sort of position coming into this as I’m not a parent of children, but it was coming in from my perspective as a pharmacist professional and as a member of society as well.  Harriet: Thank you so much, Gordon. And, last but certainly not least, Suzannah.  Suzannah: So, yes, Suzannah Kinsella. I am a social researcher at Hopkins Van Mil, and I had the pleasure of facilitating all of the workshops where we gathered together the Public Standing Group and working on reporting the outcome from our discussions, so delighted to be coming in from South London. Harriet: Thank you so much, everyone, and it’s such a pleasure to have you here today. So, many regular listeners to Behind the Genes will now that Genomics England is currently undertaking the Generation Study. I’m not going to speak about it in much detail because the Generation Study has already been the subject of several Behind the Genes podcasts and we’ll put some links to these in the show notes for this episode. But briefly, the Generation Study aims to analyse whole genomes of 100,000 newborn babies across England, looking for 250 rare conditions. We have a view to getting these children onto treatments earlier and potentially enhancing their lives.  The Generation Study is a research project because we don’t know if the application of this technology will work. And as a research project we can also answer other important questions, such as questions about a lifetime genome. When we invite parents to consent to the Generation Study on behalf of their newborn babies, we ask to store babies’ genomic data and linked healthcare data in our trusted research environment.  This helps us to further research into genes and health. But a critical question is ‘what do we do with these data long term?’ And one of the potential long-term uses of the data is to revisit it and re-analyse it over a person’s lifetime.  We could do this at critical transition points in life, like adolescence, early adulthood or older age, with the aim of using the genomic data to really enhance people’s health. But this is a very new concept. There’s been little work on it internationally, however I am pleased to say that interest seems to be picking up. In the Generation Study, whilst we are at the present time doing no lifetime genomes work, we are looking to explore the benefits, risks and potential uses of the lifetime genome.  This Public Standing Group on lifetime genomes was our first foray into this area.  So, I’d like to start off by inviting Suzannah to please explain a bit more about what the Public Standing Group is, why it was created and how a group like this helps us to generate early deliberation and insight.  Suzannah: So, the first thing I should talk about is who were these 26 people that formed part of this group, and the first thing to say is that they were a wide range of ages and backgrounds from across England, so some from Newcastle, some from London and everywhere in between. And these 26 people all had one thing in common, which is they had all taken part in a previous Genomics England public dialogue, either the whole genome sequencing for newborn screening which took place in 2021, or in a more recent one in about 2022/23 which was looking at what should Genomics England think about in terms of research access to data that’s drawn from the Generation Study. So, the great thing was that everybody had already some previous knowledge around genomics, but the concept of a lifetime genome was completely new. So these 26 people met on 5 occasions over the period of 2024, mostly meeting face to face, and really the task that they were given was to look at the lifetime genome and look at it from every angle; consent, use, information sharing and all sorts of other aspects as well. Harriet: Gordon and Suzalee, you were participants in our Public Standing Group, I’d love to hear from you what your roles in the Standing Group were and what you found most interesting, but also for you which bits were the most challenging. Suzalee, shall we start with you? Suzalee: For me the most interesting bits were being able to learn about one’s genome and, through Genomics England and their possible use of pharmacogenetics, could determine the specific medication that could be prescribed for a new health condition instead of expensive and possibly tonnes of adverse side effects trial and error medications. Additionally, as a person living with sickle cell disease, I got the chance to share my story and to give voice to people living with the same condition or similar to myself, and how the potential of the genomics newborn programme could help our future generation. There were some tricky bits, and the most challenging bit was to initially discuss and think about the idea of whether or not a parent might choose to know or not to know the potential of their newborn developing or prone to develop a certain condition based on the data received from the programme. My thought went back to when I gave birth to my first child 16 years ago and I was adamant to know if my child would inherit the sickle cell disease, what type, if it would be the trait. In my mind I knew the result, as my haemoglobin is SC and their dad is normal, but I wanted to be sure of my child’s specific trait. But then I asked myself, “What if my child was part of the Newborn Genomes Programme, then the possibility exists that other health conditions could be detected through the deep analysis of my child’s genome. Would I really want to know then? What would be the psychological effect or, in some cases, the social impact of what I have to learn?” Harriet: Tha

In this episode of Behind the Genes, we explore how ethical preparedness can offer a more compassionate and collaborative approach to genomic medicine. Drawing on insights from the EPPiGen Project, our guests discuss how creative storytelling methods, like poetry, have helped families and professionals navigate the complex emotional, ethical and practical realities of genomics. Our guests reflect on the power of involving patients and families as equal partners in research, and how this can lead to more inclusive, empathetic, and effective care. The conversation explores how ethics can be a tool for support, not just regulation, and how creating space for people to share their stories can have a lasting impact on healthcare delivery. Our host for this episode, Dr Natalie Banner, Director of Ethics at Genomics England is joined by Professor Bobbie Farsides, Professor of Clinical and Biomedical Ethics and Dr Richard Gorman, Senior Research Fellow, both at Brighton and Sussex Medical School, and Paul Arvidson, member of the Genomics England Participant Panel and the Dad's Representative for SWAN UK. Paul shares his poem 'Tap tap tap' from the Helix of Love poetry book and we also hear from Lisa Beaton and Jo Wright, both members of the Participant Panel. "The project gave us the tools to find a different way to get at all of those things inside of all of us who were going through that experience... It’s almost like a different lens or a different filter to give us a way to look at all those things, almost like a magnifying lens; you can either hold it really close to your eye and it gives you like a blurry view of the world that goes on and you can relax behind that and find a way to explore things in a funny way or an interesting way, but you can also go really close into the subject and then you’ve got to deal with the things that are painful and the things that are difficult and the things that have had an impact." You can download the transcript, or read it below. Natalie: Welcome to Behind the Genes. Bobbie: In an earlier conversation with Paul, he used the word ‘extractive,’ and he said that he’s been involved in research before, and looking back on it he had felt at times it could be a little bit extractive. You come in, you ask questions, you take the data away and analyse it, and it might only be by chance that the participants ever know what became of things next. One of the real principles of this project was always going to be co-production and true collaboration with our participants. Our participants now have a variety of ways in which they can transport their voices into spaces that they previously found maybe alienating, challenging, and not particularly welcoming. Natalie: My name is Natalie Banner, I’m the Director of Ethics at Genomics England and your host on today’s episode of Behind the Genes. Today I’ll be joined by Paul Arvidson, a member of the participant panel at Genomics England, Professor Bobbie Farsides, Professor of Clinical and Biomedical Ethics at Brighton and Sussex Medical School, and Dr Rich Gorman, Senior Research Fellow, also at Bright and Sussex Medical School.  Today, we’ll be exploring the ethical preparedness in genomic medicine or EPPiGen Project. This project examined how the promise and challenges of genomic medicine are understood and experienced by the people at the heart of it, both the clinicians providing care and the patients and families involved.  A big part of the EPPiGen Project explored using creative methods of storytelling and poetry to explore the experiences of parents of children with rare genetic conditions.  We’ll discuss why the idea of ethical preparedness is crucial in genomic medicine to acknowledge the challenges and uncertainties that often accompany the search for knowledge and treatment in genomic healthcare, and to help professionals develop the skills to navigate the complex ethical considerations.    If you enjoy today’s episode we’d love your support. Please like, share and rate us wherever you listen to your podcasts. Is there a guest you’d really like to hear on a future episode?  Get in touch at podcast@genomicsengland.co.uk. So, I’m going to ask our fantastic guests to introduce themselves.  Paul, would you like to go first? Paul: Hi, I’m Paul Arvidson. As well as my Genomics England hat, I’ve got a SWAN hat as well, I’m the dads’ rep for SWAN UK, and I’m on the poets from the EPPiGen Project.  Natalie: Brilliant to have you hear today. Thanks, Paul. Rich?  Rich: Hi, I’m Rich Gorman, I’m a Senior Research Fellow at Brighton and Sussex Medical School and I’ve been working on some of the research on the EPPiGen Project that looks at people’s social and ethical experiences of genomic medicine, and particularly families’ lived experiences of genomics.  Natalie: Brilliant. Really looking forward to hearing from you. And Bobbie?  Bobbie: Hello, I’m Bobbie Farsides, I’m Professor of Clinical and Biomedical Ethics at Brighton and Sussex Medical School and co-PI with Professor Anneke Lucasson of the Wellcome Trust funded EPPiGen Project, and it’s been my pleasure and privilege to be involved in the work that we’re going to talk about today.  Natalie: Really fantastic to have the 3 of you here today. So, we’re going to take a slightly unusual approach to starting the podcast today and we’re going to begin with Paul who’s going to read us a poem from the book Helix of Love. Paul, over to you.  Paul: This is called Tap, Tap, Tap.  ‘Tap, tap, tap, I hold the egg to my ear. There it is again, tap, tap, tap. Run to get a torch and light through the shell, to see who’s tapping from within. Chicken’s home from work these days just for fun and the odd egg. Market stalls swapped for medicines, cash boxes for cough machines. We kept the apron though. Profound learning disability is our life now, most of it, learning about it, learning from it, surviving with it, despite. It’s a subtle egg though, this. The shell is there, invisible, but there’s a person inside, tap, tap, tap.  What are you trying to tell us about what the world’s like for you? Are you bored? Do you hurt? Is your sister a love or a pain? Tap, tap, tap. I wish I could set you free.’  Natalie: Thank you, Paul. Such beautiful and powerful words. I wonder if you wouldn’t mind telling us a little bit about that poem and your journey and maybe touch on what the EPPiGen Project has meant for you.  Paul: Wow, that’s a lot to unpack in one go. I suppose the oddness of the metaphor is probably worth a mention. The way the project worked is that Bobbie and Rich collected together a proper poet, Dawn Gorman, and she led us through the process of kind of, she basically taught us all to be poets from scratch, it was… When you say it like that it was a hugely audacious project really to just collect all these randoms together in a room and throw a poet at them and see what happened.   And they trusted us, I suppose, and trusted Dawn that there was going to be something came out of this. But one of Dawn’s techniques was that like each week we did… I think we did… Did we do 6 weeks, chaps? Which felt like a huge amount of time, but it went in milliseconds. But what she did every week was that she gave us either a poetic form to work with, like, you know, “This week we’re going to learn how to do a haiku, or a sonnet,” or whatever, or she’d gone away and thought of a particular poem that she thought might resonate with us and then she’d bring that to the session. And she’d read a poem out and then say, “Right, what did you make of this? Go away and write what it inspires you to write.”    So, the poem that I wrote was, the inspiration for that session was a poem called The Egg by Richard Skinner. His poem was more about the form of the object itself, so, although that sounds really abstract, it really, really helped. So, every week it would be like Dawn threw this object into the group and said, “Right, okay, here’s your new prompt, bosh, off you go.” And although that sounds like the most obscure way to deal with anything, because you get a structure around which to organise your thoughts it was just this like hugely powerful thing for everybody.    And so, the thing that came to mind for me was the metaphor of the egg rather than the egg itself and it just kind of chimed with all of us. Like we used to run the egg stall in Minehead farmers’ market and so, I married into a country girl and so she had like 200 laying hens at one point, and so we had this whole market stall antics but also it spoke to so many things in one hit. So we gave up that part of our lives as our daughter Nenah’s condition became more and more complex.    She was always, once we knew what her genetic condition was one of the few things that we knew from the get-go was that it was progressive. So we knew in advance that that was the case, but we didn’t know what that meant. And so slowly but surely one of the things we had to do was give up our working life, you know, one week and one hour at a time, it felt. So part of the poem’s about that as well, the shift in the poem from the comedy bit to the beginning to the more serious bits at the end, and it kind of felt like we gave those things up day by day but the poem kind of got to speak to that.   And then there’s also the metaphor. Once you’ve got a good metaphor it’s always good to run with it, you know? And so the idea of the metaphor of somebody who’s got profound learning disabilities and can’t speak being inside this shell and as parents you’re always kind of peeking in from the outside to see what’s going on within or to try and find ways, the idea of when you’re checking to see if you’ve got a chick inside your shell, and you do this thing called ‘candle’ where you hold the light to it, that I describe in the poem, and you like hold it to your ear and hear if there’s movement going on inside. And you kind of, I don’t know, I felt with a profoundly learning-disabled child that

As of February 2025, the Generation Study has recruited over 3,000 participants. In this episode of Behind the Genes, we explore what we have learnt so far from running the study and how it continues to evolve in response to emerging challenges. The conversation delves into key lessons from early recruitment, the challenges of ensuring diverse representation, and the ethical considerations surrounding the storage of genomic data. Our guests discuss how ongoing dialogue with communities is helping to refine recruitment strategies, improve equity in access, and enhance the diversity of genomic data.  Our host Vivienne Parry, Head of Public Engagement at Genomics England, is joined by Alice Tuff-Lacey, Program Director for the Generation Study; Dalia Kasperaviciute, Scientific Director for Human Genomics at Genomics England; and Kerry Leeson Bevers, CEO of Alström Syndrome UK. For more information on the study, visit the Generation Study website, or see below for some of our top blogs and podcasts on the topic: Podcast: What do parents want to know about the Generation Study? Podcast: How has design research shaped the Generation Study? Blog: What is the Generation Study? "We always have to remember, don’t we, that if people say no to these things, it’s not a failure to on our part, or a failure on their part. It’s just something they’ve thought about and they don’t want to do, and for all sorts of different reasons. And the other reflection I have about different communities is the ‘different’ bit, is that what approach works for one community may not work for another, and I think that that’s something that’s going to have to evolve over length of the study, is finding the things that are the right way, the most helpful way to approach people." You can download the transcript, or read it below.   Vivienne: Hello and welcome to Behind the Genes.    Alice: “And this is quite an exciting shift in how we use whole genome sequencing, because what we are talking about is using it in a much more preventative way. Traditionally, where we’ve been using it is diagnostically where we know someone is sick and they’ve got symptoms of a rare condition, and we’re looking to see what they might have. What we’re actually talking about is screening babies from birth using their genome, to see if they are at risk of a particular condition, and what this means is this raising quite a lot of complex ethical, operational, and scientific and clinical questions.”    Vivienne: My name’s Vivienne Parry, and I’m Head of Public Engagement here at Genomics England, and I’m your host on this episode of Behind the Genes.      Now, if you are a fan of this podcast, and of course you’re a fan of this podcast, you may have already heard us talking about the Generation Study, the very exciting Genomics England research project which aims to screen 100,000 newborn babies for over 200 genetic conditions using whole genome sequencing.      Well, we’ve got more on the study for you now. What we’re doing to make it both accessible and equitable for all parents-to-be, and our plans to ensure that we continue to listen to parents, and perhaps in future, the babies as they grow up. We’ll chat, too, about emerging challenges and how we might deal with them.    I’m joined in our studio by Alice Tuff-Lacey, the Programme Director for the Generation Study, and Dalia Kasperaviciute, Scientific Director for Human Genomics, both from Genomics England, and we’re delighted to welcome Kerry Leeson-Bevers, Chief Executive of Alström Syndrome UK. And I’m just going to quickly ask Kerry, just tell us about Alström Syndrome and how you’re involved.    Kerry: Yes, so Alström Syndrome is an ultra-rare genetic condition. My son has the condition and that’s how I got involved. So, the charity has been around now since 1998, so quite a well-established charity, but as part of our work we developed Breaking Down Barriers, which is a network of organisations working to improving engagement and involvement from diverse, marginalised and under-served communities as well.    Vivienne: And you wear another hat as well?  Kerry: I do. So, I’m also a member of the research team working on the process and impact evaluation for the Generation Study. So, I’m Chair of the Patient and Public Involvement and Engagement Advisory Group there.    Vivienne: Well, the multiply hatted Kerry, we’re delighted to welcome you. Thank you so much for being with us.      So, first of all, let’s just have a sense from Alice Tuff-Lacey about this project. In a nutshell, what’s it all about, Alice?  Alice: Thanks Viv. So, I think in the last few years we’ve seen some really big advances in the diagnoses of rare diseases through things the Genomic Medicine Service. But we know it takes about 5 years often to diagnose most of these rare conditions. What we also know is that there are several hundred of them that are treatable, and actually there can be massive benefits to the child’s health from diagnosing and treating them earlier. I think a really good example of this which is often talked about is spinal muscular atrophy, which is a particular condition where there is a genetic treatment available and there is a really big difference in families from those babies where the condition was identified later on, versus their brothers and sisters where they were identified early because they knew there was a sibling that had it and they were given that treatment.     What we think there is a huge potential opportunity to identify these children from their genome before they get ill, and this is quite an exciting shift in how we use whole genome sequencing, because what we are talking about is using it in a much more preventative way.  But this is a really different approach to how we’ve been using it so far, because traditionally where we have been using it is diagnostically where we know someone is sick and they’ve got symptoms of a rare condition and we are looking to see what they might have, what we are actually talking about is screening babies from birth using their genome to see if they are at risk of a particular condition. And what this means is, this raises quite a lot of complex ethical, operational and scientific and clinical questions.      So the aim of the Generation Study is really to understand if we can and should use whole genome sequencing in this way to screen for rare conditions in newborn babies. We’ve been funded by the Department of Health and Social Care to do this over the following years, and the way we’ll be doing this is by a national study across a network of trusts in England where we are aiming to recruit about 100,000 babies and screen them for rare treatable conditions that we know present in childhood. And really the aim of this is to understand if this will work and how it will work, and to generate the evidence to allow the NHS and the National Screening Committee to decide if this could become a clinical service, and that’s very much the primary goal of the study.      Beyond that, however, there are some other aims of the study, and we also consent mothers to ask permission to retain their genomic data and to link it to the baby’s clinical data over their childhood, and we’ll be providing access to this to researchers in the de-identified way in our trusted research environment. And this is to really understand if that data can also be used to further generate information around other discovery research, but also critically understand that the motivations for parents involved will be very different, and we need to think very carefully about how we engage and work with the parents of the babies going forward about how we use their data.    Vivienne: And the super exciting thing is we’ve started recruiting. How many mothers have we recruited?  Alice: So, we’ve recruited over 3,000 to date, and it’s building every day and every week really. And it’s really exciting because we see more and more trusts coming online and the study building and really starting to learn from the experience. And every week and every month, we’re learning much more about how this process works, what the impact it’s having, and kind of what we need to do over the coming few months and years to deliver it.    Vivienne: And we did a huge about of work at Genomics England before the study even started, to try and find out what people wanted. So, we found out, for instance, that people didn’t want to know about late onset conditions, they did want to know about conditions where there was a treatment, and they wanted things that could be done for their babies in childhood. So, we had a really clear steer from the public about this project before we even started. So, how are we continuing to learn from the people who are involved in the study and the public? I mean Kerry, you’ve been involved in this aspect. We need to listen, don’t we, to find out what’s going on?    Kerry: We do, we do, and I think it’s really encouraging to see the public dialogue and the amount of engagement work that was done there to kind of identify what some of those areas were, but it’s really important that we don’t stop that engagement there. It’s really important to continue that, and I know that we’ve got quite a diverse group for our Patient and Public Involvement Advisory Group and the Evaluation Team, and one of the things they’re really interested in is how we’re going out there to speak with communities. You know, we can’t just be reliant on the media, and press releases about the study. We need to actually go to communities and have these conversations so that people can have a conversation within an environment that they feel safe and confident with the people that they feel supported by as well.    So I think it’s really key that we continue to ask those questions but also learning from the evaluation and, as we go through the process, of speaking to the patient organisations as well who support families that su

Rare condition research is evolving, and patient communities are driving the breakthrough. In this special Rare Disease Day episode, we explore the challenges and opportunities shaping the future of rare condition therapies. From groundbreaking gene therapy trials to the power of patient-driven research, our guests discuss how collaboration between families, clinicians, researchers, and regulators is paving the way for faster diagnoses, equitable access to treatments, and innovative approaches like nucleic acid therapies and CRISPR gene editing. With insights from Myotubular Trust, we follow the journey of family-led patient communities and their impact on advancing gene therapy for myotubular myopathy - showcasing how lived experience is shaping the future of medicine. However, while patient-driven initiatives have led to incredible progress, not every family has the time, resources, or networks to lead these research efforts. Our guests discuss initiatives like the UK Platform for Nucleic Acid Therapies (UPNAT), which aims to streamline the development of innovative treatments and ensure equitable access for everyone impacted by rare conditions. Our host Dr Ana Lisa Tavares, Clinical lead for rare disease at Genomics England, is joined by Meriel McEntagart, Clinical lead for rare disease technologies at Genomics England, Anne Lennox, Founder and CEO of Myotubular Trust and Dr Carlo Rinaldi, Professor of Molecular and Translational Neuroscience at University of Oxford. "My dream is in 5 to 10 years time, an individual with a rare disease is identified in the clinic, perhaps even before symptoms have manifested. And at that exact time, the day of the diagnosis becomes also a day of hope, in a way, where immediately the researcher that sent the genetics lab flags that specific variant or specific mutations. We know exactly which is the best genetic therapy to go after." You can download the transcript, or read it below. Ana Lisa: Welcome to Behind the Genes.    [Music plays]  Anne: What we’ve understood is that the knowledge and experience of families and patients is even more vital than we’ve all been going on about for a long time. Because the issue of there being a liver complication in myotubular myopathy has been hiding in plain sight all this time, because if you asked any family, they would tell you, “Yes, my son has had the odd liver result.”  There were some very serious liver complications but everybody thought that was a minor issue, but if we are able to engage the people who live with the disease and the people who observe the disease at a much more fundamental level we may be able to see more about what these rare genes are doing.  [Music plays]  Ana Lisa: My name is Ana Lisa Tavares, I’m Clinical Lead for Rare Disease research at Genomics England and your host for this episode of Behind the Genes. Today I’m joined by Anne Lennox, Founder and CEO of the Myotubular Trust, Dr Meriel McEntagart, an NHS consultant and Clinical Lead for Rare Disease Technologies at Genomics England, and Dr Carlo Rinaldi, Professor of Molecular and Translational Neuroscience at the University of Oxford.    Today we’ll be hearing about the importance of involving the patient community, particularly as new rare therapies are developed, and discussing the forward-facing work that’s happening that could have potential to unlock novel treatments for many rare conditions.  If you enjoy today’s episode we’d love your support. Please like, share and rate us on wherever you listen to your podcasts. Thank you so much for joining me today.  Please could you introduce yourselves.   Anne: I’m Anne Lennox, I’m one of the founders of the Myotubular Trust, a charity that raises research funds for and supports families affected by the rare genetic neuromuscular disorder myotubular myopathy.  Meriel: I’m Meriel McEntagart, I’m a consultant in clinical genetics in the NHS and I have a special interest in neurogenic and neuromuscular conditions.  Carlo: Hi, I’m Carlo Rinaldi, I’m Professor of Molecular and Translational Neuroscience at the University of Oxford. I’m a clinician scientist juggling my time between the clinic and the lab where we try to understand mechanisms of diseases to develop treatments for these conditions.  And I’m also here as a representative of the UK Platform for Nucleic Acid Therapies, UPNAT. Thanks for your invitation, I’m very pleased to be here.  Ana Lisa: Thank you. Meriel, I’d love you to tell us a bit about your work and how you met Anne, how did this story start?  Meriel: Thank you. Well prior to being a consultant in clinical genetics, I spent 2 years as a clinical research fellow in neuromuscular conditions, and as part of that training I worked on a project where the gene for myotubular myopathy had just been identified, and so there was a big international effort to try and come up with sort of a registry of all the genetic variants that had been found as well as all the clinical symptoms that the affected patients had, and then do kind of a correlation of the particular variant mutation with symptoms.   I worked when I was training to be a clinical geneticist because of my interest in neuromuscular conditions so when I eventually became a consultant at St George’s Hospital I was actually interviewed by the Professor of Paediatrics and he knew Anne and her son, when Anne was looking for more information about the condition he suggested that perhaps I might be a good person for Anne to talk to.  Ana Lisa: Thank you. Interesting connections. Anne, can you tell us your story and how this led you to found the Myotubular Trust?  Anne: Yes, thanks Ana-Lisa.  Well, as many families will tell you when they’re newly diagnosed with a rare disease, you go from knowing nothing about a condition to being one of the few deep experts in that condition because there are so few deep experts. So this happened to us in 2003 when our son, Tom, was born, and when he was born he was floppy and his Apgar scores, the scores they do on new-born babies, were pretty poor, and before long we knew that it was more than just momentary issues at birth.  And, cutting a very long story short, 5 weeks later he was diagnosed with this very rare neuromuscular genetic disorder that we didn’t know we had in the family.  We were told that this was a very serious diagnosis.    At that time – more than 20 years ago – over 80% of those boys didn’t make it to their first birthday and the stark statistic we had in our head a lot was that only 1% made it past the age of 10. And that has changed due to better ventilator and breathing equipment, etc, but at the time we expected that he might not make it to his first birthday.    We were very lucky, we had Tom longer than one year, we had him for nearly 4 years, 4 very lovely years where it was tough, but he was a really lovely member of our family.  Despite being really weak he managed to be incredibly cheeky and bossy, and he was a great little brother for his big sister. We were also very lucky that he was being looked after by Professor Francesco Muntoni, who is Head of the Paediatric Neuromuscular Service at Great Ormond Street. And, like Carlo, he is a clinical researcher and actually that I found to be amazing as a family member because you knew what was happening out there and Professor Muntoni, other than living with the reality day to day you want to know where things are going.    We began to realise that back then 20 years ago the more common rare neuromuscular diseases were finally beginning to get some fundamental research funds, like Duchenne, spinal muscular atrophy, and Professor Muntoni was very good at explaining to lay non-scientific parents like us that one day the technologies that would lead to a cure, that would re-engage proteins for other conditions and would translate down eventually into the possibility of replacing myotubularin, which is the protein not being produced or not being produced enough in myotubular myopathy. And then we began to understand actually what the barriers to that would be, that translating developments in more common, or let’s say more prevalent conditions, would be hard to do without some translation research being done; you could not just not lag years behind, you could lag decades behind if you haven’t done some other work.    So, I met Wendy Hughes, another mother, of a boy called Zak who was a few years older than Tom, and these were the days before social media, and it was amazing to be in contact with another family going through something similar and we had great conversations. But then they were also looked after by Professor Muntoni and we particularly began to develop the idea as 2 families that we might be able to raise some research funds towards this concept of keeping pace with the scientific developments.  And then we discovered there was no charity we could channel those funds through. Even the umbrella body for neuromuscular diseases who were covering 30 to 40 conditions, frankly, they just couldn’t trickle their funding down into investing in every neuromuscular disease, and slowly but surely it dawned on us that if we did want to make that difference we were going to have to set up our own charity.   So that’s what we eventually did and back in 2006, we founded what was actually the first charity in Europe dedicated to myotubular myopathy – luckily, more have come along since – and we were dedicated to raising research funding. In fact, it wasn’t our goal to set up another charity but around that time, about a year in, we happened to go to a meeting where the Head of the MRC, the Medical Research Council, was giving a talk and he said that in the last few years the MRC had begun to really realise that they couldn’t cure everything, that they couldn’t cure the diseases that would be cured in the next millennium from a top down perspective. There had to be a trick, there had to be a bottom up as well, because that was the only way

In this episode, our guests explore the impact of genetic discoveries on inherited retinal dystrophies, in particular retinitis pigmentosa (RP). The discussion highlights a recent study that identified two non-coding genetic variants linked to RP, predominantly in individuals of South Asian and African ancestry. The conversation highlights how advances in whole genome sequencing are uncovering previously hidden causes of genetic disease, improving diagnostic rates, and shaping the future of patient care. It also addresses the challenges faced by individuals from diverse backgrounds in accessing genetic testing, including cultural barriers, awareness gaps, and historical underrepresentation in genomic research. Our host Naimah Callachand is joined by researcher Dr Gavin Arno, Associate Director for Research at Greenwood Genetic Centre in South Carolina, Kate Arkell, Research Development Manager at Retina UK, and Bhavini Makwana, a patient representative diagnosed with retinitis pigmentosa and Founder and Chair of BAME Vision. We also hear from Martin Hills, an individual diagnosed with autosomal dominant retinitis pigmentosa. To access resources mentioned in this episode: Access the Unlock Genetics resource on the Retina UK website Visit the BAME vision website for more information and support Find out more about the groundbreaking discovery of the RNU4-2 genetic variant in the non-coding region which has been linked to neurodevelopmental conditions in our podcast episode   "Discoveries like this lead to better clinical management. We understand better the progression of the disease when we can study this in many individuals from a wide spectrum of ages and different backgrounds. We can provide counselling as Bhavini was talking about. We can provide patients with a better idea of what the future may hold for their eye disease, and potentially, you know, we are all aiming towards being able to develop therapies for particular genes and particular diseases."   You can download the transcript or read it below. Naimah: Welcome to Behind the Genes.   Bhavini: The few common themes that always come out is that people don’t really understand what genetic testing and counselling is. They hear the word counselling, and they think it is the therapy that you receive counselling for your mental health or wellbeing. There is already a taboo around the terminology. Then it is lack of understanding and awareness or where to get that information from, and also sometimes in different cultures, if you have been diagnosed with sight loss, you know blindness is one of the worst sensory things that people can be diagnosed with. So, they try and hide it. They try and keep that individual at home because they think they are going to have an outcast in the community, in the wider family, and it would be frowned upon).  Naimah: My name is Naimah Callachand and I am Head of Product Engagement and Growth at Genomics England.  I am also one of the hosts of Behind the Genes. On today’s episode I am joined by Gavin Arno, Associate Director for Research at Greenwood Genetic Centre in South Carolina, Kate Arkell, Research Development Manager at Retina UK, and Bhavini Makwana, patient representative.  Today we will be discussing findings from a recently published study in the American Society of Human Genetics Journal which identified two non-coding variants as a cause of retinal dystrophy in people commonly of South Asian and African ancestry. If you enjoy today’s episode, we’d love your support. Please like, share, and rate us on wherever you listen to your podcasts.  Okay, so first of all I would like to ask each of the three of you to introduce yourselves. Bhavini, maybe we’ll start with you.  Bhavini: Hi, I’m Bhavini Makwana, patient representative, and also Chair of BAME Vision. I have other roles where I volunteer for Retina UK, and I work for Thomas Pocklington Trust.  Naimah: Thanks Bhavini. Gavin.  Gavin: Hi, my name is Gavin Arno, I am Associate Director for Research at the Greenwood Genetic Centre in South Carolina, and I am Honorary Associate Professor at the UCL Institute of Ophthalmology in London.  Naimah: Thanks Gavin. And Kate.   Kate: Hi, I’m Kate Arkell, Research Development Manager at Retina UK.   Naimah: Lovely to have you all today. So, let’s get into the conversation then. So Gavin, let’s come to you first. First of all, what is retinitis pigmentosa and what does it mean to have an inherited retinal dystrophy?  Gavin: So, retinitis pigmentosa is a disorder that affects the retina at the back of the eye. It is a disease that starts in the rod photoreceptor cells. So, these cells are dysfunctional and then degenerate causing loss of peripheral and night vision initially, and that progresses to include central vision and often patients will go completely blind with this disease. So, retinal dystrophies are diseases that affect the retina. There are over 300 genes known to cause retail dystrophy so far, and these affect different cells at the back of the eye, like retinitis pigmentosa that affects the rods. There are cone rod dystrophies, ones that start in the cone photoreceptors, macular dystrophies that start in the central retina, and other types of retinal dystrophies as well.  Naimah: Thanks Gavin. And Bhavini, just to come next to you. So, you received a diagnosis of retinitis pigmentosa at the age of 17 after a genetic change was found in the RP26 CERKL gene. At this time only ten other families in the UK had been identified with this type of genetic alteration. Would you mind sharing a bit more about your journey to your diagnosis?  Bhavini: Yeah. So, at the age of 17 is when I got officially diagnosed with retinitis pigmentosa, but leading up to that I was experiencing symptoms such as night blindness. So, I struggled really badly to see in the dark, or just in dim lighting, like this time of the year in winter when it gets dark quite easily, all my friends from college could easily walk across the pavement, but I struggled. I was bumping into a lot of things. Like things that I wouldn’t really see now that I know my peripheral vision, I was losing that, so like lamp posts or trees or bollards, I would completely miss or bump into them. I was missing steps, and had a really, really bad gaze to the sun. Like, everything was really hazy. That continued and I just put it down to stress of exams. You know, just given that age and where I was at the time of my life. But then it kind of continued. So, I went to the see the optician who then referred me, and after months of testing I got diagnosed with retinitis pigmentosa. Back in the late 90s when I was diagnosed there wasn’t really anything about genetic testing, or cures., or treatments. I was basically just told to get on with it, and that was it.   It was only until about 15/16 years later I came across Retina UK, started understanding what retinitis pigmentosa is, and what it means, and then when I was offered genetic testing and counselling at one of my annual Moorfields appointments, they explained to me what it involved, what it could mean, what kind of answers I would get, and I agreed to take part. It was a simple blood test that myself and both my parents took part in.      Naimah: Thanks for sharing that Bhavini. So, I know you were able to receive a diagnosis through whole genome sequencing in the 100,000 Genomes Project after the alteration in the gene was found, and this was found in the coding region of the genome. But in this study that we are talking about in this podcast, we know that the two genetic changes that were found, they were in the non-coding region of the genome. Gavin, could you tell me in simple terms what the difference is between the coding and non-coding region of the genomes and why these findings are significant in this case?   Gavin: Yes, sure. So, the human genome is made up of about 3 billion letters or nucleotides which are the instructions for life essentially. Now, within that human genome there are the instructions for roughly 20,000-25,000 proteins. This is what we call the coding genome. These are the bits of DNA that directly give the instructions to make a protein. Now, we know that that part of the genome is only roughly 2% of the entire genome, and the remaining 98% is called the non-coding genome. Now, we understand that far less well. We have a far poorer understanding of what the function of the non-coding genome is versus the coding genome. So, typically molecular diagnostic testing or genetic testing is focused on the coding genome, and historically that has been the fact. Now with advances in genome technologies like whole genome sequencing and the 100,000 Genomes Project, we are able to start to look at the non-coding genome and tease out the previously poorly understood causes of genetic diseases that may lie within those regions of the genes.   Naimah: Thanks Gavin, I think you have just really highlighted the possibilities available with looking at the non-coding region of the genome.  Kate, coming to you next. I wanted to talk about the importance of uncovering and understanding genetic causes of inherited retinal dystrophies, and how do discoveries like these change the landscape of care for patients with inherited retinal dystrophies?  Kate: So, getting a genetic diagnosis can really help families affected by inherited retinal dystrophy. It helps them and their ophthalmologists to better understand their condition, and in some cases gain some insight into possible prognosis, which helps people feel a lot more in control. It can also potentially inform family planning decisions and even open up options around access to reproductive technologies for example, not only for the individual, but sometimes also for their close relatives. Of course, researchers are making great strides towards therapies, some of which have reached clinical trials. But a lot of these approaches are gene specific, so for people wh

In this episode, our guests discuss the potential of large-scale health datasets to transform research and improve patient outcomes and healthcare systems. Our guests also delve into the ethical, logistical, and technical challenges that come with these programmes. We hear how organisations such as UK Biobank, Our Future Health, and All of Us are collecting rich, diverse datasets, collaborating and actively working to ensure that these resources are accessible to researchers worldwide. Hosting this episode is Dr Natalie Banner, Director of Ethics at Genomics England. She is joined by Dr Raghib Ali, Chief Medical Officer and Chief Investigator at Our Future Health, Professor Naomi Allen, Professor of Epidemiology at the Nuffield Department of Population Health, University of Oxford, and Chief Scientist for UK Biobank, and Dr Andrea Ramírez, Chief Data Officer at the All of Us Research Program in the United States. "There are areas where academia and the NHS are very strong, and areas where industry is very strong, and by working together as we saw very good examples during the pandemic with the vaccine and diagnostic tests etc, that collaboration between the NHS and academia industry leads to much more rapid and wider benefits for our patients and hopefully in the future for the population as a whole in terms of early detection and prevention of disease." You can download the transcript or read it below.  Natalie: Welcome to Behind the Genes   Naomi: So, we talked to each other quite regularly. We have tried to learn from each other about the efficiencies of what to do and what not to do in how to run these large-scale studies efficiently. When you are trying to recruit and engage hundreds of thousands of participants, you need to do things very cost effectively. How to send out web-based questionnaires to individuals, how to collect biological samples, how the make the data easily accessible to researchers so they know exactly what data they are using.   All of that we are learning from each other. You know, it is a work in progress all the time. In particular you know, how can we standardise our data so that researchers who are using all of us can then try and replicate their findings in a different population in the UK by using UK Biobank or Our Future Health.    Natalie: My name is Natalie Banner, and I am Director of Ethics at Genomics England. On today’s episode we will be discussing how we can unlock the potential of large health datasets. By that I mean bringing together data on a massive scale, including for example genomic, clinical, biometric, imaging, and other health information from hundreds and thousands of participants, and making it available in a secure way for a wide range of research purposes over a long time period.   Through collaboration and industry partnerships, these programmes have the potential to transform research and deliver real world benefits for patients and health systems. But they also come with challenges ranging from issues in equity and ethics through to logistics, funding, and considerable technical complexities. If you enjoy today’s episode, we would love your support. Please like, share, and rate us on wherever you listen to your podcasts.     I’m delighted to be joined today by 3 fantastic experts to explore this topic. Dr Raghib Ali, Chief Medical Officer and Chief Investigator at Our Future Health. Professor Naomi Allen, Professor of Epidemiology at the Nuffield Department of Population Health, University of Oxford, and Chief Scientist for UK Biobank, and Dr Andrea Ramírez, Chief Data Officer at the All of Us Research Program in the United States.   Andrea, if I could start with you. It would be really great to hear about All of Us, an incredibly ambitious programme in the US, and maybe some of the successes it has achieved so far.   Andrea: Absolutely. Wonderful to be here with you and thank for you for the invitation. The All of Us Research Program started in 2016 from the Precision Medicine Initiative and was funded with the goal of recruiting 1 million or more participants into a health database. That includes information not only from things like biospecimens including their whole genome sequence, but also surveys that participants provide, and importantly linking electronic health record information and other public data that is available, to create a large database that researchers that access and use to study precision health.   We have recruited over 830,000 participants to date and are currently sharing available data on over 600,000. So, we’re excited to be with your audience, and I hope we can learn more and contribute to educating people listening about precision medicine.   Natalie: Thank you, Andrea. And not that this is competitive at all, but Raghib, as we are recording this, I understand the Our Future Health programme is marking quite a phenomenal milestone of 1 million participants. Would you mind telling us a little bit about the programme and something that you see as the benefits of working at scale for health research.   Raghib: Thank you very much. So, Our Future Health is a relatively new project. It was launched in 2020 with the aim of understanding better ways to detect disease as early as possible, predict disease, and intervene early to prevent common chronic diseases. Similar to All of Us, we are creating a very large database of participants who contribute their questionnaire data, physical data, genetic data, and linkage to healthcare records, with the aim as I said, to really improve our understanding of how best to prevent common chronic diseases.   So, we launched recruitment in October 2022. Our aim is to recruit 5 million participants altogether, and in the last 2 years about 1.85 million people have now consented to join the project. But you are right, as of last week we have what we call 1 million full participants, so people that have donated a blood sample, completed the questionnaire, and consented to link to their healthcare records. In our trusted research environment, we now have data on over 1million people available for researchers to use.   Of course, we have learnt a lot from the approach of UK Biobank, which we are going to hear about shortly, but the resource is open to researchers across the world, from academia, from the NHS, from industry, so that will hopefully maximise the benefits of that data to researchers, but as I say with a particular focus on early detection, early intervention, and prevention research.   Natalie: Thank you Raghib. Great to have you with us. Naomi, Raghib mentioned that UK Biobank has been running for a long time, since 2006.  It is a real success story in terms of driving a huge range of valuable research efforts.  Could you talk to us a little bit about the study and its history and what you have learned so far about the sort of benefits and some of the challenges of being able to bring lots of different datatypes together for research purposes?   Naomi: Yeah, sure. So, UK Biobank started recruiting 0.5 million participants in 2006 to 2010 from all across the UK with a view to generating a very deep dataset. So, we have collected information on their lifestyle, a whole range of physical measures. We collected biological samples, so we have data on their genomics and other biomarkers. Crucially because they recruited 15+ years ago, we have been able to follow up their health over time to find out what happens to their health by linkage to electronic healthcare records. So, we already have 8,000 women with breast cancer in the resource, cardiovascular disease, diabetes, and so on.   But perhaps most importantly, not only does it have great data depth, and data breadth, and the longitudinal aspect, is the data is easily accessible to researchers both from academia and industry, and we already have 18,000 researchers actively using the data as we speak, and over 12,000 publications already generating scientific discoveries from the resource.      Natalie: So, we have got 3 quite different approaches. Recruiting in different ways, different scale, different depth of data collection and analysis, but all very much around this ethos of bringing lots of different datatypes together for research purposes. I wonder if you could talk a little bit about how you might be sort of working together, even though you have got slightly different approaches. Are there things that you are learning from one another, from these different data infrastructures, or how might you be looking in the future to work together to address some of the challenges that might come up from working at scale?      Naomi: So, we talk to each other quite regularly. We have tried to learn from each other about the efficiencies of what to do and what not to do in how to run these large-scale studies efficiently. When you are trying to recruit and engage hundreds of thousands of participants, you need to do things very cost effectively. How to send out web-based questionnaires to individuals, how to collect biological samples, how to make the data easily accessible to researchers so they know exactly what data they are using.   All of that we are learning from each other, and you know it is a work in progress all the time. In particular, how can we standardise our data so that researchers who say are using All of Us can then try and replicate their findings in a different population in the UK by using UK Biobank or Our Future Health. So, can we come up with common standards so that researchers can better directly compare the data that they are using? So, we are in close contact with each other.   Natalie: Fantastic, thank you. And Andrea, from your perspective obviously you are collecting data in the US. Are you finding ways of working internationally and with other infrastructures like Biobank and Our Future Health around things like data standards? It sounds like something simple, but I can imagine it is quite complex in practi

In this explainer episode, we’ve asked John Pullinger, Senior Bio Sample Operations Manager at Genomics England, to explain what it means to go on a diagnostic odyssey. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. The episodes mentioned in the conversation are linked below. Hope for those with no primary findings The impact of a genetic diagnosis on mental health You can download the transcript or read it below. Florence: What does it mean to go on a diagnostic odyssey? I'm joined by John Pullinger, Senior Bio Sample Operations Manager for Genomics England to find out more. So, John, first of all, can you explain what we mean by diagnostic odyssey?   John: Yes, of course. The diagnostic odyssey is a term used to describe the journey that many people with rare conditions and their families undertake to receive an accurate diagnosis, a journey that takes on average over five and a half years.  The rarity of the condition means that there are few, if any, other people affected by it, for doctors to draw their experience from. Some individuals might never receive a diagnosis.  My job involves making sure that samples sent through the Genomics England processes can travel smoothly from the NHS hospitals to be sequenced and the results be reported back to the individual. We try and minimise the amount of time that samples and associated data is in our care.   Florence: And for people listening who might not know, could you explain why it sometimes takes a long time for people to receive a diagnosis?  John: There are estimated to be over 7,000 rare conditions.  This means that healthcare professionals may not be familiar with all of them and so may not recognise them or know how to test for them. In addition to this, some conditions affect multiple parts of the body. For example, skin, the heart, and the lungs. In these cases, there will be a need to visit specialists from multiple departments, and each will be looking specifically at their own area.  This could lead to referral loops where the patient needs to consult multiple healthcare professionals, all of which contributes to the time taken to receive a diagnosis. Since, for the majority of rare conditions, there is an underlying genetic cause. This means that most individuals who get a diagnosis will receive one through genomic testing, whether that be whole genome sequencing as offered here at Genomics England, or more targeted panel testing.  Typically testing will identify a particular gene, which is known to be linked to a specific condition. For certain conditions, it requires a real expert in the condition to even think about testing for it. Sometimes a condition will present in a way that is different to most other people who have it. So they may have symptoms that others don't. This also adds to the buildup of time taken to receive the diagnosis.  Florence: So, you mentioned earlier, John, that the diagnostic odyssey lasts an average of five and a half years. Can you explain what kind of effect this long waiting time has on individuals and their families?  John: Absolutely. One aspect of the diagnostic odyssey that is important to recognise is the physical effect of the as yet undiagnosed condition that's present and affecting the individual and their family on a daily basis. Those with rare conditions may be affected by a range of emotions connected to the ongoing journey that they're on, including feelings of isolation.  Also stress and anxiety. The fear of unknown can have a massive knock-on effect on the mental health of the individual and their family. And it's important to recognise the signs of this so that people can take steps to manage their mental health. Many rare conditions first present themselves in children and young adults, so considering the effects on their day-to-day lives is especially important.  Florence: If you'd like to learn more about how the diagnostic odyssey can affect someone, listen to our previous podcast, “Hope for those with no primary findings”, where Participant Panel member Lisa Beaton, shares her experience of awaiting a diagnosis for her daughter. And so, John, can we talk now about what happens at the end of a diagnostic odyssey?  John: A section of the odyssey that is essential to understand is potentially getting a diagnosis. It may come as a surprise to think that the diagnosis can sometimes be scary as well as a potential relief to the family and also the individual involved. But this reason the work of genetic counsellors is crucial to help those with rare conditions, understand and adapt to the medical, psychological, and potential reproductive implications of their new diagnosis.   Florence: Our previous podcast, “The impact of a genetic diagnosis on mental health” covers this topic in much more detail. So for my final question today, I wanted to ask whether there are ways that families or individuals affected by rare conditions can access support.  John: We would recommend that anyone who might be going through a diagnostic odyssey who wants to know more about their care to contact their doctor or other healthcare professionals in their genetics team, additional resources are also available online, including the NHS website and charities such as Genetic Alliance UK and SWAN UK.  There are also lots of brilliant patient communities and groups that you can get support from.   Florence: That was John Pullinger explaining what it means to go on a diagnostic odyssey. If you'd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk.  Thank you for listening.

The Genetic Rare Syndromes Observational Cohort (GenROC) study aims to improve our understanding of how rare genetic conditions affect the way children grow, their physical health and their development. Through actively involving parents as experts in their child's condition, the study seeks to gather valuable insights and ensure that family experiences shape future research and care strategies. You can find out more about the study and eligibility criteria via the Bristol University website. In this episode, Jillian Hastings Ward, patient advocate and former Chair of the Participant Panel at Genomics England, is joined by Dr Karen Low, a clinical geneticist leading the study at the University of Bristol, who shares insights into its objectives, the importance of a co-production approach with families, and the vital data being collected in the study to improve support for these children and their families. We'll also hear from Lindsay Randall, a parent who discusses the journey of receiving a rare diagnosis for her child, highlighting the critical need for more comprehensive information and community support. "If you join GenROC, that data will be used to develop a growth chart for your child essentially and their genetic condition, so I’m really excited about it because I feel like that’s a very concrete definite given now for all the families in GenROC, which is just brilliant." You can download the transcript or read it below. Jillian: Welcome to Behind the Genes Lindsay: Historically, there’s been a significant absence of patient voice in rare disease research and development, and knowing that’s changing, I think that’s really empowering for families and to know that professionals and industry are actually listening to our stories and unmet needs and really trying to understand, and that offers much greater impact on the care and treatments of patients in the future. Jillian: My name is Jillian Hastings-Ward. On today’s episode I’m joined by Dr Karen Low, Consultant Clinical Geneticist and Chief Investigator for the General Cohort Study, and Lindsay Randall, Paediatric Practice Development Nurse and founder of Arthur’s Quest, which is a UK registered, non-profit, raising awareness for the ultra-rare condition: SLC6A1, developmental and epileptic encephalopathy. Welcome to you both. Today we’ll be discussing the GenROC study, which is aiming to understand more about the health, development and valuing the experiences of children with neurodevelopmental conditions. If you enjoy today’s episode we’d love your support. Please like, share, and rate us on wherever you listen to your podcasts. Thank you both very much for joining us today, Karen and Lindsay. There’s a lot we want to cover, but first of all it would be great just to put a little bit of context around the Gen-Roc study. Karen, can you tell us a bit about what the study is aiming to do, who is eligible and why do you want them? Karen:  Thank you. And thank you so much for having me today, Jillian. So, the GenROC study, first to just explain to people what ‘GenROC’ stands for. GenROC stands for the Genetic Rare Syndromes Observational Cohort Study. Just to give you some context about the study, I’m a clinical geneticist and most of my clinical work focuses on paediatrics, so I see children in my clinics and the sort of children I see generally are children with rare genetic syndromes. The last five to ten years we’ve got much better at diagnosing children with these rare conditions and that’s because testing has got so much better. We can now do whole genome sequencing and we can do that on the NHS, which is amazing, children can get their tests as part of their clinical care, so it means that a lot more children are being diagnosed with rare conditions, about 2,000 per year in the UK. And the thing about that is, that I see these children in my clinics and I give their families that diagnosis. But the problem is for so many of these ultra-rare conditions, like Lindsay’s family has, we sit there and we say to the family, “Well, your child has got ‘X’ condition,” and we give them some information from maybe one or two publications and linked to a leaflet and a Facebook group. And then we say, “But really we don’t know that much about this condition.” And they say, “But what is it going to mean for them when they are growing up or when they are adults? Will they be able to finish school? Will they be able to work? What is it going to mean?” And I have to shrug my shoulders and go, “I’m not really sure.” And as a geneticist and as a doctor and as a mother really, I just felt that wasn’t good enough, and I found it really frustrating and I know that the families that I work with, that I look after, also find it frustrating and I wanted to do better. And I also found it frustrating that for many genes, researchers would publish two or maybe three publications about these conditions, and then they would move on to the next novel gene, and actually, the journals are a bit like that as well, they like novel things, they like new conditions, they like the next gene. And so, it means that actually data doesn’t always carry on being gathered in these rare conditions, and there are a lot of them. That was another thing, I sort of felt that these conditions were being done a disservice and that we needed to do better, so that’s where the whole idea of the GenROC study came from was my drive and desire to improve things for families and actually to work with families to improve that, and that’s where so this is a very highly co-produced study and right from the outset I’ve involved parents in telling me what they wanted to know and I’ve got a very, very active PPI group, full of parents of children who have got rare genetic conditions, and also I’m really lucky to have a young adult who has a genetic neurodevelopmental disorder herself and they all tell me about essentially what I should do and what I shouldn’t do. They tell me when I’m not doing enough or when I need to do something differently, so it’s very highly co-produced, they’re highly involved all along the way. So, children with a confirmed genetic diagnosis in a list of eligible genes which people can see on our website if they Google GenROC University of Bristol, we’ve got a very easy checker for eligible genes, but they are essentially the most frequently diagnosed genes in rare neurodevelopmental disorders. And if their child is under 16, has a confirmed diagnosis and doesn’t have any other genetic diagnoses then they can go into the GenROC study, that’s essentially the eligibility criteria. Jillian: That’s really interesting. It’s very helpful to hear the background and I think as a parent of a child with a very rare disorder hearing that the clinicians also recognise this gap and the sort of pause that happens once you have your initial diagnosis, is really helpful and really encouraging. Lindsay, can we turn to you next and can you unpack a little bit about what it meant for you to get a rare diagnosis for your child and what point on your family journey was that compared to where you are now? Lindsay: I think to get a rare diagnosis for us was difficult and challenging and I think the first kind of challenge that any family has is actually being well-informed by a paediatrician who is also well-informed, and that’s not always the case. That can affect the way we acknowledge or accept a diagnosis and how we also access support and how we understand what more we can do to make more connections. We did have genetic counselling offered, but I think there are families out there who don’t get genetic counselling offered to help them understand the child’s diagnosis, and then there’s a heavy reliance on the internet, and as you said, there’s a lack of information out of there. A lot of conditions are newly diagnosed or they’re very complicated genes to work with, or as Karen said, they’ve had a couple of papers and people have moved on. And I think that does cause an immense feeling of isolation. We were diagnosed in 2018, our son, our first child, and exactly as Karen said, it was a fairly quick appointment of, “We don’t really know much about this condition at the moment, there’s a couple of papers. We know of 34 children in the world at the moment with your condition. Here’s a Facebook group,” which we did join. And it is overwhelming to be given a diagnosis that’s delivered with such little hope I guess, finding sources of information that’s valid and robust is challenging, not everyone knows how to do that or has a skillset to conduct searches of academic research and I think that clinicians could definitely do better in also signposting the kind of umbrella charities like Unique and Contact and Swan and patient organisations, because I know that would have been definitely helpful for us as a family to be able to have opportunities to connect with others. Jillian: Thank you. Our diagnostic journey has been a bit a similar in that we were diagnosed through the NHS, and that at the time my son was the first person diagnosed with his disorder in the whole of the UK so it was really a big question mark, it was a question of our geneticist saying, “Here’s the three PDF articles that we know exist in the world about this condition. Can you read them and tell us whether you think that sounds like him in order for us to be confirming our diagnosis?” I very much hear what you’re saying there about feeling lost in the wilderness. And we too joined a Facebook group quite shortly after we got our diagnosis, and at the time my son was among the older ones or certainly as time has gone by he has been among the older children, so it can be really hard to know what might happen next. I think that now as Karen was saying we’re getting much better at diagnosing people thanks to all the extra testing that’s happening, that happens much earlier in life than it has done in the past, but I think then it still leaves a

As 2024 comes to a close, we take a moment to reflect on what has been a busy year at Genomics England and in the wider genomics community. Throughout the year, guests have joined us to discuss groundbreaking research discoveries, important ethical considerations, and share their personal stories. It was also a year of transformation: we rebranded our podcast as Behind the Genes, welcomed Dr Rich Scott as our new Chief Executive Officer, and launched the Generation Study, in partnership with NHS England. The Participant Panel also saw changes, with Kirsty Irvine stepping into the role of Chair and Adam Clatworthy and Helen White becoming Vice Chairs. In this special end of year episode, Adam Clatworthy, Vice-Chair of the Participant Panel, sits down with Dr. Rich Scott, CEO of Genomics England, to look back on the highlights of 2024. Together, they revisit key podcast moments, reflect on research discoveries, and share insights into the evolving world of genomics. Below are the links to the podcasts mentioned in this episode, in order of appearance: Celebrating genomic breakthroughs - Insights from the Festival of Genomics Shining a light on rare conditions How has a groundbreaking genomic discovery impacted thousands worldwide? How can we work in partnership towards a new era of genomic medicine and research? How has design research shaped the Generation Study? How can we bridge the gap between diverse communities? Can Artificial Intelligence accelerate the impact of genomics? "It's really important that we just continue to bring that patient and participant community on that journey, just to ensure that they really understand the full benefits. And we've talked about that on the episode today. I know that the panel has always encouraged the Genomics England team to look at its boots while shooting for the moon. I really like that phrase just to make sure, look, we can't forget where we've come from to make sure we're taking people on that journey" You can download the transcript or read it below. Adam: Welcome to Behind the Genes.  Rich: Our vision at Genomics England is a world where everyone can benefit from genomic healthcare, thinking about how we ensure the lessons we’ve learnt through our diverse data programme is embedded across all of our work.  So that word “everyone” applies to people in lots of different ways, different communities people come from, different socioeconomic backgrounds, making sure that equity is baked into all of our work.  And there’s real opportunity for genomics to play a broader role than in rare conditions and in cancer, we’re proud of the impact we’re already having there, and we should really look to the future.  Adam: My name is Adam Clatworthy, and I’m the Vice-Chair for rare conditions on the Participant Panel at Genomics England.  On today’s episode, I’m going to be joined by Rich Scott, CEO of Genomics England.  We’re going to be taking a look back at the key milestones from 2024 for Genomics England, and really discussing our hopes and aspirations for the year ahead.  During this episode we’ll also hear from some of our guests we’ve had on the show this year, who have helped shape our discussions and shared some of their most impactful moments and insights.  And if you’d like to listen to more like this, then please subscribe to Behind the Genes on your favourite podcast app.  So, with that, thanks for joining me, Rich, how are you doing?  Rich: I’m great, thanks for hosting today, I’m really excited about it.    Adam: So, Rich, it’s been a pretty exciting year for you, you’ve taken on the CEO role at Genomics England full-time, so why don’t you just start by telling us about how those first few months have been for you?  Rich: It’s been a really exciting year, I think for us overall at Genomics England, and obviously personally taking on the CEO role, which is an enormous privilege.  I’ve been at Genomics England nine years, and I think both a privilege and a real responsibility to take on the role.  To think both about how we continue to honour the commitments we’ve given our participants and those we work with, and to think about the future, where we might go together, what evidence we need to generate, what our systems need to support.  So it’s been great taking on the role, and thinking about that, both the present and the future, and there’s been lots, as we’ll talk about, there’s been lots going on.  Adam: No, that’s great.  And I must say for myself as well, I started the Vice-Chair role at a very similar time to you early in the year.  When I started, we were in the process of looking for our next Chair.  Obviously, we had Jillian and Rebecca, both standing down, after many years in the role.  They’ve been there from the start, really guiding the Panel through this amazingly successful period.  But for me, I’ve really enjoyed working in partnership with Helen, who is our Vice-Chair for cancer.  It’s been a real partnership, in terms of filling in for that interim leadership role.  And we wanted to make sure that we weren’t just caretakers, we were really continuing to be actively involved in a lot of the discussions that are happening with your colleagues across Genomics England.  Very much leading the Panel, and starting to have those important discussions around, where does the Panel go next?  And what’s our strategy for the next two to three years?  What are the key areas that we can drive real value and impact, in line with your own milestones at Genomics England?    And, of course, I’ve just loved getting stuck into chairing the Panel meetings as well, for me, that’s the best part, is really bringing together these amazingly diverse and passionate people.  With so many different personalities, lived experiences, and a combined passion for just taking this forward together, and making sure that the benefits of genomics really impact, and that’s felt by the wider community itself.  So there’s been lots of highlights to recognise this year, a real stand-out for me has to be the Genomics England Research Summit, from what I understand it was the most attended event to date.  And it was just so good to see that a lot of the Panel were front and centre across that event, sharing their stories, having a really active role, whether introducing speakers, or telling their own journeys as part of the Q&A sessions.   I myself was really privileged to be on stage with Baroness Nicola Blackwood, literally nine days after I officially started the role.  So it was great to just dive in at the deep end, get in front of an incredible audience, and just see that the broader Panel was front and centre of the event itself.  And it was just great to see how popular the event was, many more people coming to have a chat to us on the stand than would have found us before, so, all in all, a really big highlight for myself.  So, for you, Rich, are there any other highlights that you want to call out for this year?  Rich: And first to say, absolutely agree with the Research Summit being, you know, a highlight.  The diversity of the discussions that we had, it’s one of the things we enjoy most about thinking about creating the summit, as you say, involving the participants very much at the centre.  Like, physically at the centre of the room, for people to come and talk to participants and hearing stories.  And then really seeing how over the years we can see the impact growing, and having talks, whether it’s about individual findings, or big research studies.  So the final talk of the day was from Charlie Swanton.  He was talking about some really exciting work that his team have done in our National Genomics Research Library, making a really important discovery about extra chromosomal DNA in cancer, and that’s now been published in Nature.  And then right next to him, we were having a policy talk from Sam, who’s the CEO of NICE.  And you can see the range of things, the sorts of evidence, sorts of conversation, we need to have, so that was really fantastic.  I’d call out one discovery this year that maybe we’ll come back to, and one other big highlight.  So I think the big discovery this year was the discovery of this piece of non-coding sequence in the genome called RNU4-2, which turns out to be pretty much the most common cause of developmental disorders that’s been discovered.  And it’s just so exciting to see that having been discovered in the National Genomics Research Library.  And then the news, the knowledge spread, across the world, and family support groups coming together to understand and learn more about what that means for them.  So that was, I think, the discovery over the years at Genomics England that’s touched me most, seeing that story.  And I’d say for us, organisationally, another big highlight has been the launch of our newborns programme, the Generation Study.  So as lots of people listening will know, we’ve been actually thinking about what the questions underlying this study are for a good number of years, doing a lot of preparatory work.  Actually, before we even started, setting up public dialogue jointly with the National Screening Committee about what the public were keen to understand and the appetite for research in this area.  And then we’ve been spending several years designing the study, working with the NHS how to design, safely launch it, National Screening Committee involved all along, and working with patients and the public to design it.  And this year now launching the study at a public launch, just a couple of months ago, by the time people are listening to this, and at the time of recording, more than 2,000 families have joined the programme.    So really exciting, us exploring a really big question for genomics, about the use of whole genome sequencing in newborn babies.  Whether that should be offered to every baby at birth, primarily driven by that desire to do better for those children born with treatable conditions, where genetics,

In this explainer episode, we’ve asked Katrina Stone, Clinical Genetics Doctor, and Clinical Fellow at Genomics England, to explain what happens when you go for whole genome sequencing for a rare condition. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What happens when I go for whole genome sequencing? I'm joined by Katrina Stone, Clinical Genetics Doctor, to find out more. So, Katrina, first things first. What is the purpose of whole genome sequencing?   Katrina: The purpose of whole genome sequencing is to try to make a precise genetic diagnosis for someone with a suspected or confirmed genetic condition.  Florence: And why might someone get whole genome sequencing?   Katrina: They might get whole genome sequencing because they are known to have a condition which is likely to be genetic, but the medical team wants to find out what the exact genetic cause is. In other cases, the diagnosis might not be known, and the reason for doing whole genome sequencing is to find out whether there is a genetic condition present.  Some of the benefits of having the test is that. If a condition is identified, this can provide an explanation for the family about what's been going on, and it can also bring to an end further unnecessary investigations. Also, if a genetic diagnosis is confirmed, this can sometimes point towards other things which might need to be kept an eye on for the individual.  In addition, once a diagnosis is confirmed, a doctor can advise the family on the likelihood of other members of the family or future children being affected with the same condition, and they can use this information to help with future family planning.  Florence: So, then what happens when a person physically goes to get the test?   Katrina: In most cases, an individual will see a specialist doctor. This might be a genetics doctor, but it could be a doctor specialising in another body system. They'll do a full assessment of the individual, including finding out lots of information about them and their family, and also examining them to look for any clues that might point towards a specific genetic diagnosis.  Once the family have decided to go ahead with the test, their consent will be taken, where the test will be explained in more detail, including the pros and cons of going ahead with the test and after that samples can be taken. Usually this is a blood sample, but occasionally a saliva sample or cheek swab could be taken.  The best way to perform whole genome sequencing is with a sample from the person being tested along with both of their parents. And the reason for this is that it makes it easier to separate out genetic changes that are more likely to be significant from those that just represent harmless genetic variation what makes us all unique.  Florence: What happens to this sample after the test has taken place?   Katrina: So, the blood samples will go to a genetics lab where the genetic material known as DNA is extracted. The DNA is then sequenced, so we get an electronic file of all their genetic information. This is then analysed firstly by a computer which picks out changes or variants in their DNA, which are more likely to be significant.  After this, a trained clinical scientist analyses the data in detail. Sometimes there isn't a clear-cut result, and the scientists might need help from others and interpreting the result, but if there is, they can create a report which details the likely diagnosis.  Florence: And finally, how will the patient get the result from their whole genome sequencing test?  Katrina: Usually, the result is fed back to the patient and their family by the clinician who arranged their testing or one of their close colleagues. It's important to note that not everyone will get a genetic diagnosis from the test. This doesn't necessarily mean there isn't a genetic diagnosis present.  There are several reasons why tests might be negative. One is that no test is perfect and something important might have been missed because of the way the test works. Or it may be that the person being tested has a change in a gene that hasn't been described as causing a disease before, so we wouldn't even know to look for it.  There's also a possibility that there isn't a single genetic cause for their symptoms. Rather, lots of minor genetic factors are causing their condition. We're not very good at testing for these yet. Finally, there could be a non-genetic cause that just hasn't been identified yet.  One of the benefits of having a whole genome sequencing test is that the data can be stored and looked at again in the future, either in light of new evidence or once our knowledge of genetics has improved.  Florence: That was Katrina Stone explaining what happens when you get whole genome sequencing. If you'd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk.  Thank you for listening.

In this episode, we explore the importance of patient involvement in shaping rare condition research initiatives. Our guests discuss why it’s crucial to involve individuals with lived experiences, including patients and caregivers, in setting research agendas. In doing so, this approach ensures research can be more inclusive, efficient, and impactful, addressing the issues that matter most to those affected. Mel Dixon, Founder Cure DHDDS and member of Genomics England Participant Panel is joined by Jo Balfour, Founder of CamRARE and Dr Rona Smith, Senior Research Associate at the University of Cambridge and Honorary Consultant in Nephrology and Vasculitis. Find out more about the Cambridge Rare Disease Research Network, discussed in the episode, which aims to support the rare condition community in building an online network of partnerships and resources to facilitate new patient-centred research opportunities. "We’re really turning research on its head, moving away from it being a researcher-led activity where they decide on the idea and the research concept and bring patients in at different points along that research journey and instead starting with the patient’s idea in the first place.  It can only be a better system for all because it improves efficiency, it improves potentially the long term outputs and, most importantly, outcomes for patients." You can download the transcript or read it below. Mel: Welcome to Behind the Genes. Rona: I think it really means that we measure what matters to patients and individuals that are affected.  Often, it’s really difficult to capture kind of the real impact of disease and there’s a tendency for researchers to measure things that are easy to measure and are reproducible, which of course is important but what’s most important is actually being able to truly capture the impact of an intervention on an individual’s condition.  So, I think that’s another key aspect of having people with lived experience involved right from the start. Mel: My name is Mel Dixon and I’m a member of the Participant Panel at Genomics England and founder of Cure DHDDS, a charity set up to raise awareness, support families and help drive research into the ultra-rare DHDDS gene variant.  On today’s episode I’m joined by Jo Balfour, Managing Director of CamRARE, which is the Cambridge Rare Disease Network.  This network unites patients, advocates, experts and leaders to address the challenges faced by people affected by rare conditions.  I’m also joined by Rona Smith, Associate Professor at the University of Cambridge and honorary consultant in nephrology and vasculitis.  Today we’ll be discussing the role of patients in setting research agendas and how their involvement can lead to more impactful and patient-centred research.  If you enjoy today’s episode we’d love your support.  Please like, share and rate us on wherever you listen to your podcasts. Before we begin the interview I’d like to share a little bit of my story.  In November 2022, following whole genome sequencing, we received the news that two of our three children carried a neurodevelopmental and neurodegenerative DHDDS genetic variant.  At the time of our children’s diagnosis there was very little information on our gene, minimal research happening into it and no treatment pathway.  Through our charity, Cure DHDDS, we have worked tirelessly to instigate research and create a collaborative scientific research community.  I am a huge advocate for patient-led research and have witnessed first-hand the positive impact it can have on patient lives.  Thanks to the work of the many scientists that we have had the honour of collaborating with, within two years of our children’s diagnosis we have a disease-modifying therapy in our sight and an ASO (Antisense oligonucleotides) therapy in development.  We are incredibly grateful for the opportunities genetic testing has given us but I also appreciate how overwhelming a genetic diagnosis can be and how challenging it can be for families to initiate research projects with little to no resources, and that’s why initiatives such as CamRARE that we’ll be discussing today are so important.   On that note, let’s get back to our podcast guests.  I wonder before we dive into today’s topic if you could both give a brief introduction, and, Rona, if you could also give the less scientifically-minded of us an explanation about what nephrology is. Rona: Thank you for inviting me today.  So I’m Rona Smith, I work in Cambridge and I’m a nephrologist and that means somebody that looks after individuals who have diseases that affect their kidneys.  My specialist interest is in something called vasculitis which is a rare autoimmune disease that affects all organs in the body but kidneys as well.  Mel: Thank you.  And Jo?  Jo: Hi Mel.  I’m Jo Balfour, the Managing Director and one of the founding members of Cambridge Rare Disease Network, or CamRARE for short.  I think we’re often described as the ‘Chief Everything Officers’.  I manage the charity and all of our operations and our wonderful team.    Mel: Lovely.  Thank you very much.  Rona, I wonder also if you could explain to our listeners what is a research agenda?  Rona: So in brief a research agenda is really a strategy that outlines key questions or topics that a research community, and that might be investigators, clinicians, scientists, patients, industry,  and they are the priorities that they want to explore and address over a period of time.  So it’s really a direction of travel and identification of areas of importance and where there are gaps in knowledge so that it then leads to the opportunity to form specific research questions that you can then go on and address.  Mel: Why do you both think it’s important to involve patients in setting these research agendas?  Jo: Well I think critically one of the things that I’ve learnt over my time working, not just in the rare disease sector but also earlier in social care and education, is that we should as professionals never assume anything; you know, we have not lived in their shoes and we don’t know what the daily life of people living with rare conditions is like.  So gathering that day to day lived experience is really crucial.  And I have a unique opportunity to see into that daily life with our local community of rare disease families who have a range of different rare conditions.  I’m party to their conversations, to their daily trials and tribulations, the things that are difficult, the things that they find joy in but I still will always go back to them and ask their opinion.  I see myself as a spokesperson for them as we’re an umbrella organisation but I certainly never really know what it’s like to live with their conditions.  I think they bring with them diverse experiences which we really need and value in setting research priorities, they have unique knowledge of their own conditions.  They ethically have a right to be involved from the start and to set that priority and agenda but, equally, it’s valuable for us as researchers because if we can involve people early we have definitely more chance of good engagement and later success, better outcomes for everyone.  Mel: Couldn’t agree more.  And, Rona, is there anything you’d like to add to that? Rona: I think it really means that we measure what matters to patients and individuals that are affected.  Often it’s really difficult to capture kind of the real impact of disease and there’s a tendency for researchers to measure things that are easy to measure and are reproducible, which of course is important but what’s most important is actually being able to truly capture the impact of an intervention on an individual’s condition.  So I think that’s another key aspect of having people with lived experience involved right from the start.  Jo: Another thing that’s actually quite interesting that I’m going to mention here is that I think when you live day in, day out with a condition your perception of things like pain is different from your average person’s so you become almost accepting of your daily norm, and I think that’s really critical to understand as well.  And it’s only by getting to really know patients and understand. When we say, “What’s your pain like on a scale of 1 to 10?” you know, something that I feel as pain because I get it rarely I probably am going to put it at a higher score than somebody who has that every day.  So I think there’s subtleties and nuances like that as well which are really critical to get across by conversation with patients.  Mel: That makes absolute sense.  And I see that from the patient perspective myself.  I was out with my friends the other day and they said, “Oh my goodness, you’re constantly taking your children to sports activities.”  Because of their physical needs we’re constantly,  they go to Pilates, they go to swimming, they go to gym class – we try to keep them fit and healthy – and we, even though they’re older, have to take them there and back and that’s become our norm but when you’re speaking to families whose children don’t have those difficulties they have no idea how much time that actually takes up.  And I had no idea how much like time it takes up compared to what other people are doing because that is our norm, that’s what we’ve accepted as the norm.  Patients and patient groups are incredibly driven and invested in their rare disease as well so they make really good rare disease research partners.     And, moving on, what do you see as the challenges and barriers to patient involvement and how do we overcome these? Rona: I think probably the biggest barrier is time.  So, the most important thing is investing time to build relationships, to really understand in-depth perspectives both from the patient’s side but also the researcher’s side. And, inevitably, we always want to do things faster and actually this is one really, really critical aspect is investing time.  Funding is also a

In this explainer episode, we’ve asked Meriel McEntagart, Clinical Geneticist in the NHS and Clinical Lead for Rare Disease Technologies at Genomics England, to explain how genetic conditions can be inherited, and other ways they may arise. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. To learn more about X-linked inheritance, as mentioned in the episode, tune in to our explainer episode, how does X-linked inheritance work? You can download the transcript or read it below. Florence: Are genetic conditions always inherited from parents? I'm joined by Meriel McEntagart, clinical geneticist for the NHS to find out more. So, Meriel, first things first. How can a genetic change cause a condition?   Meriel: We have about 20,000 genes. That's the estimate and they are the code or blueprint for how to grow and develop a human being. And, if you think about a code, you can have a mistake in a code or a variant in a code. And if that happens, such as one genetic letter being changed for another, the result can be that the code doesn't give the correct instructions about how to grow and develop that human being. There are lots of different ways in which those changes can happen.  Florence: And how can we inherit conditions from our parents?   Meriel: Well, for the most part, like I mentioned, we've got 20,000 pairs of genes and we get one of each pair from our mother and our father. And so, for lots of genetic conditions, they follow a pattern of inheritance where one copy of that pair of genes has got the variant or spelling mistake in it, which causes the condition.  So just having a single mistake in that pair of genes is enough to cause you to develop the symptoms of the condition. Other conditions show where you only develop the condition if both copies of the pair, the one you get from your mother and the one you get from your father have got a variant or a spelling mistake in the gene.  So, you actually don't have a working copy of that gene. There are other patterns of inheritance as well. And so, we talk about X-linked inheritance. That can arise because women have what we call two X chromosomes; men only have one X chromosome.  Florence: If you want to learn more about X-linked Inheritance, you can check out our previous podcast. How does X-linked inheritance work? So then do parents who have a condition always pass it on to their children?  Meriel: So, this is again, where we think about some of those patterns of inheritance that I've just mentioned. If somebody has a condition, for example, a dominant condition, they will have that variant or genetic change that's causing their condition in one of their pair of genes. So then it's 50:50 when they have a child, whether they pass on the gene that's carrying that variant or not, because the child will be getting the other copy of that pair from their partner.  If they do inherit that copy with the variant in it, then they will develop the symptoms of the condition in most cases. In some situations, however, a parent can have a genetic condition. So, they develop symptoms of the condition, and as I've mentioned, it's 50:50, whether it gets passed onto the child, so the child could actually inherit that genetic variant, but potentially not show signs of the condition. And this is what we call ‘reduced penetrance’. This means you can carry a genetic variant and probably some other event has to take place to cause you to develop symptoms.  So that might be that there's other genetic factors that you inherit that trigger you to develop symptoms or there might be an illness or something that you experience that brings out the expression of that gene. So that's quite an important, consideration when we're looking at genetic variants and whether somebody will develop symptoms.  Florence: And finally, how do we develop conditions that don't come from our parents?  Meriel: Well, I suppose the main explanation for that is what we call a de novo genetic event. So that can arise when we are conceived. So for example, genes get copied to be put into the sperm or our genes get copied to be put into the egg. And in that process of making the sperm and the egg, a spelling mistake or mutation can arise in the DNA and then that sperm or that egg, whichever one has it, takes that forward into making the baby. And then the baby from that point will have that genetic variant in every single cell in their body. So it hasn’t come from the parents, so it’s not inherited but it still is a genetic condition. This is something that now that we're able to do whole genome sequencing, we are finding is a more common explanation for developmental disorders or conditions in children than we previously appreciated. And quite a lot of conditions where the child has congenital abnormalities when they're born, like a congenital heart problem with some global development delay or difficulties or some other sort of problem, when we do their whole genome sequencing, we find that they have a de novo mutation in an important developmental gene.  There are also some more unusual ways in which a genetic condition can arise for the first time in the family. The first example I might give is, the condition, Huntington's disease. Huntington's disease is a neurodegenerative condition that causes a movement disorder, often starting in adult life. And sometimes people will know that it's in their family. However, sometimes it can arise in somebody and there's no history of it in the family at all.  Huntington's disease is what we call a triplet repeat condition. This is where, in our DNA sometimes we have little strings of letters that are repeating after each other. So, usually we'd have 25 repeats or less. This can slip up on transmission from a parent to the child, so it can increase in size and if it slips up into the range of 40 repeats or more, then that person will develop symptoms of the condition.  Another example I thought that might be worth mentioning is what we call imprinting. When we inherit our genes from our parents, for some genes, it actually matters whether the gene copy has come from your mum or from your dad, and it will have an imprint or a mark on it that says, this is the maternal copy, this is the paternal copy.  The reason that imprint is there is that it may potentially switch off that gene and say, this shouldn't be expressed in the baby. And if this doesn't work properly, you can get some conditions like for example, Prader-Willi Syndrome. This is where a child has developmental delay and maybe a very increased appetite. And it's because the differential gene expression hasn't worked. Florence: That was Meriel McEntagart, explaining whether genetic conditions are always inherited. If you would like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.

In this episode, we explore findings from a groundbreaking study recently published in Nature which revealed potential targets for bowel cancer prevention and treatment. The study provides the most detailed understanding yet of bowel cancer’s genetic makeup. The research, which used data from the 100,000 Genomes Project identified over 250 genes that play a crucial role in the condition, driver genes and potential drug targets. Our guests discuss the potential impact of these findings on patient outcomes, screening for bowel cancer, and future prevention strategies. Helen White, Participant Panel Vice-Chair for Cancer at Genomics England is joined by Professor Ian Tomlinson, Professor of Cancer Genetics at the University of Oxford, Claire Coughlan, Clinical Lead for Bowel Cancer UK and consultant nurse in colorectal cancer, and Dr David Church, a clinical scientist fellow and a medical doctor specialising in oncology at Oxford University. "The people that were kind enough to donate samples to the 100,000 Genomes Project, they did so knowing that they almost certainly wouldn’t benefit personally from their donation from their gift and that any benefits would be some way down the line and hopefully benefit others which is what we’re seeking to realise now. But, you know, it’s not a given when we treat people in the clinic so we’re very, very grateful to those individuals." You can read more about the study in our colorectal cancer blog and our study findings news story. You can download the transcript or read it below. Helen: Welcome to Behind the Genes. Ian: One of the great hopes is that some of these new genes that we’ve found could be useful in preventing cancer and it doesn’t necessarily matter that they’re rare, even if they’re only 1% of cancers, by using those and changing those in the normal individual before they have had cancer then we may be able to reduce that risk. So, there are lots of potential new targets for prevention that are coming through.  My name is Helen White and I’m the Participant Panel Vice-Chair for Cancer at Genomics England. Today I’m delighted to be joined by Professor Ian Tomlinson, Professor of Cancer Genetics at the University of Oxford, Claire Coughlan, Clinical Lead for Bowel Cancer UK and consultant nurse in colorectal cancer, and Dr David Church, a clinical scientist fellow and a medical doctor specialising in oncology at Oxford University.   Today we will be discussing a pioneering colorectal cancer study which using data from the 100,000 Genomes Project has uncovered new insights that could transform diagnosis and treatment for patients with bowel cancer. If you enjoyed today’s episode we would love your support, please like, share and rate us on wherever you listen to your podcast.  Thank you for joining me today. We’re going to be discussing the findings from a landmark study that has been published in nature. This study used data generously donated by people with bowel cancer who took part in the 100,000 Genomes Project giving us the most detailed look yet at the genetic makeup of colorectal cancer better known as bowel cancer. But before we get into that let’s start by hearing from my guests. Could each of you please introduce yourselves.  Ian: I’m Ian Tomlinson, I work at the University of Oxford and most of my work is research into bowel cancer, it’s genetic causes, the genes that are involved in actually causing the cancer to grow which may be different from genetic causes and also the use of that data to help patients whether guiding future treatments or potentially helping to prevent bowel cancer which would obviously be our optimum strategy to have the biggest impact on the disease and its incidents.   Claire: So, I’m Claire Coughlan, I’m the clinical lead for Bowel Cancer UK and my remit at the charity is to ensure that everything we do is clinically relevant and that we’re providing services that meet the needs of those affected by bowel cancer and the educational needs of those health professionals that work with people affected by bowel cancer. I’m also a nurse consultant in colorectal cancer at Lewisham and Greenwich NHS Trust and I lead an urgent referral service there and also work with patients with late effects of bowel cancer.  David: I’m David Church, I’m a medical oncologist and Cancer Research UK advanced clinician scientist at the University of Oxford. I treat bowel cancer clinically and do research on bowel cancer and womb cancer including a lot of research using samples and data from Genomics England data service we’re discussing today of course.  Helen: Great, thank you. Now let’s turn to Claire to learn more about bowel cancer. Claire, can you share with us how common it is, how treatable it is and if there are any trends in terms of which groups of people are affected?  Claire: Of course, bowel cancer is a relatively common cancer, there are about 46,000 people each year in the UK diagnosed with bowel cancer so that is quite a large number. The thing that really drives us forward in bowel cancer is that the earlier stage you’re diagnosed at the greater chance of survival. So, the figures for that are quite stark, we stage bowel cancer through stage one to 4 with one being the earliest stage and 4 being the most advanced.   If you are diagnosed with bowel cancer at stage one you have a 9 in 10 chance of being alive and well 5 years after your diagnosis of bowel cancer. And if you’re diagnosed at the other end of the spectrum at stage 4 that drops to a 1 in 10 and should people survive after a diagnosis of stage 4, which more people than before do they will have had a lot of treatment for their bowel cancer so the burden of the treatment will also be with them after that. So, it’s really important that we diagnose at the earliest possible stage which is why studies such as the one we’re going to talk about today are so important.   We have noticed that there has been a slight increase in being diagnosed at a younger age. That said the latest statistic is 2,600 people were diagnosed under the age 50 in the UK last year so it’s still a disease of older people, you still have a greater chance of getting bowel cancer as you get older but it’s really, really important that we’re aware that you can still get bowel cancer as a younger person.   Probably one of the most exciting things that has happened for bowel cancer of recent years is our bowel cancer screening programme and the age for that now has been brought down to 50, we’re not quite there all over the country, but in the UK that is the aim that everyone will be screened for bowel cancer at the age of 50. So, yes it’s a common disease and staging an early detection is vital. Helen: That’s lovely Claire, thank you very much for that. David, turning to you could you please explain to us how bowel cancer typically develops? David: Yes, so we know compared with many cancer types quite a lot about how bowel cancer develops because the bowel is accessible to collect samples by a technique called endoscopy which is putting a camera into the bowel from which you can sample tumours or lumps. And so from genetic research done in the last 10 years we know that, or we’ve known for many years actually, for much longer, that cancer is a genetic disease, it’s a disease caused by alterations in genes and particularly genes that control whether the cells in our bowel grow normally and die normally as they should do. And collectively when there are alterations in genes that regulate those processes you can have a cell or collection of cells which are able to grow without restraint and don’t die when they should do which are some of the hallmarks of a cancer and they also require the ability to spread elsewhere in the body which is what kills people with cancer including bowel cancer. We know from research done in the last 10 to 15 years that some of the alterations in genes that can cause bowel cancer in combination occur very early in our life, even in the first and second decade of life, but don’t cause cancer. The earliest detectable abnormality is typically a polyp which is a tumour, a lump within the bowel which is detectable and if removed is almost certainly cured by removal alone but if it’s not detected then as that grows and acquires more alterations in genes then it can become a cancer and cancers develop the ability to invade the bowel wall, to spread to what we call lymph nodes or glands nearby and also to spread further afield, most commonly to the liver or to the lungs.   And for most people whom bowel cancer has spread to the liver or to the lungs or elsewhere unfortunately we’re not able to cure their disease which as Claire has said is why there is such an importance in detecting cancers and pre-cancers as we call them so that the tumours are not actually cancerous but come before bowel cancer as early as possible.  Helen: Thank you David. Moving on to the study, Ian perhaps you can take this, in the study that you carried out my understanding is that the whole genome sequencing was used to investigate the genetic changes that lead to the development and growth of bowel cancer. And for this participants with bowel cancer in the 100,000 Genomes Project donated both a blood sample and a tumour sample while those with rare conditions only provided a blood sample, can you explain why that is?  Ian: As you said the study really looked at 2 quite separate arms albeit with a little bit of overlap as we’ll see. So, one very important aim was to look at individuals, both children and adults, who had medical problems or other conditions that were unexplained but which had some features that suggested that they weren’t necessarily inherited but there may be some variation in their genes that had caused them, and roughly half of the programme was dedicated to that.   Within that there was a small number of people who had a strong family history of bowel cancer or who had large numbers of polyps in the b

In this explainer episode, we’ve asked Adrianto Wirawan, Director of Bioinformatics Engineering at Genomics England, to explain what the term 'no primary findings' means. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What does ‘no primary findings’ mean? I'm joined by Adrianto Wirawan, Director of Bioinformatics Engineering for Genomics England, to find out more. So firstly, Adrianto, when we speak about findings from genomic tests, what does this mean? What are we looking for when we do a genomic test?  Adrianto: Our DNA is made up of a long sequence of letters that act like instructions for your body.  Genomic testing analyses these letters to see if there are any unusual patterns or changes that might change your health. You can imagine your DNA as a book full of recipes for your body. Every recipe tells your body how to make proteins that keep you healthy, and sometimes there might be a typo in the recipe, like missing an ingredient or mixing up the steps. This could result in a health problem, just like how a changed recipe can lead to a bad dish.  On average, we would expect about 5 million out of our 3 billion DNA letters to be different. And each of these, we call them a genetic variant. Genomic testing is designed to examine some of these variants to help inform our healthcare. So, for example, in understanding why certain health problems happen and in choosing the best treatment based on our unique genetic makeup.  Florence: And what do we mean by primary findings?  Adrianto: Primary findings mean that in a patient's genomic testing, we identified a set of variants that is linked to the patient's condition. The variants that we have makes us who we are. However, not all of them cause a disease or contribute to a health problem. our bioinformatics pipelines will automatically prioritise variants of potential relevance to the patient's conditions. Using this data, the NHS clinical scientists will then determine whether any of these prioritised variants are linked to the patient's condition and whether a genetic diagnosis has been identified, which would explain why certain health problems happen.  Florence: So, then what happens when there are no primary findings?   Adrianto: When no primary findings are found, that means that no genetic diagnosis has been identified. As developments are made and our knowledge of the variance improves over time, additional findings might be identified in the future.  The clinical team responsible for a patient's care may request reanalysis of data according to the national guidance, following a change in the patient's clinical status to inform reproductive decisions, or after significant new disease gene associations have emerged.  In addition, Genomics England also provides the diagnostic discovery pathway where we focus on uncovering new diagnosis, where the participants of the 100,000 Genomes Project, as well as the patient's sequenced through the NHS Genomic Medicine Service   This is meant to be more equitable as we don't rely on the clinical teams to raise individual separate requests.  Florence: And finally, what do we mean by secondary findings?   Adrianto: Secondary findings are additional findings not related to the conditions in which the patient was recruited for. For example, if a patient was recruited for one type of cancer, but perhaps we found variants linked to a different condition. We explored secondary findings for the 100,000 Genomes Project but we do not do secondary findings for the Genomic Medicine Service.   Florence: That was Adrianto Wirawan explaining what we mean by ‘no primary findings’. If you'd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk.  Thank you for listening. 

In this explainer episode, we’ve asked Mathilde Leblond, Senior Design Researcher for the Generation Study at Genomics England, to answer some frequently asked questions that we received from parents who we engaged with for the design of the study. You can hear more information about Generation Study via the study's official website and in our previous podcast episodes: How has design research shaped the Generation Study? Which conditions will we look for initially in the Generation Study? You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. You can download the transcript or read it below. Naimah: You may have heard about the Generation Study. This research study led by Genomics England in partnership with NHS England will sequence the whole genomes of a hundred thousand newborn babies and will look for more than 200 rare conditions that could be treated in the NHS in early childhood.  The study seeks to improve how we diagnose and treat rare genetic conditions to enable babies and families to have better outcomes. Today I'm joined by Mathilde Leblond, who leads design research for the Generation Study, and will be answering some of the frequently asked questions that we receive from parents who we engaged with for the design of the study — the same questions that expectant parents at participating hospitals might have before deciding if they want to take part.  So first of all, Mathilde, can you tell me a little bit more about your role?  Mathilde: Hello. So, I'm a design researcher. My role is to support my colleagues, understand our users deeply so that we can create experiences that are as positive and seamless as possible.  So today we'll talk about the parents who are the ones invited to take part in the Generation Study, but our users also include the midwives who are approaching them and taking blood samples. The clinical scientists who are interpreting the results and the specialist paediatricians will be contacting the parents if a condition is suspected, and even many more users actually.  So, we did a lot of research prior to launching to shape the Generation Study, and now that we're live, we continue doing more to keep improving the experience.  Naimah: Okay, so can you give us a bit of background? How did you engage with parents in this study?  Mathilde: Yeah, so today we've involved over 150 pregnant and recent parents in our co-design sessions.  And these sessions were slightly different each time with different topics and exercises, but generally we spend around 90 minutes with one parent. And we asked them to bring someone who helped them make decisions about their baby during their pregnancy. So that meant that we had their mums, their sisters, their husbands, their wives and friends as well, taking part and discussing the Generation Study with us.  During that time with them, we would test our materials. We listened out to what's important to them and what they asked about, and we got them to show us what would work better for them so that we could then shape the materials around that.   Naimah: So you can find out a bit more about why it's important to involve users in co-design in our podcast ‘How has design research helped shape the Generation Study?’, which is available on our website.   So, we have a list of frequently asked questions from some of the parents, and I wanted to post some of them to you today, Mathilde. So first of all, one of the questions was, why should my baby take part in this study?  Mathilde: Yeah, I mean, that's really the key questions that all parents are asking themselves before they even spend any time finding out more about the Generation Study. And our materials do reflect that. So what tends to matter most to the parents we spoke to, is that there's a small chance that their baby may benefit directly from taking part because if a condition is suspected, they'll be invited for further specialised tests within the NHS, and they could receive treatment much sooner than if we had waited for the symptoms to develop and for a diagnosis to come, which can sometimes take years for some rare conditions. But for a large majority of the babies, 99%, they will have no condition suspected and so their involvement really is more altruistic. Taking part means that their parents agree to share the baby's healthcare records on an ongoing basis and their genome with researchers who can then look at this together with information from thousands of other babies and patients to help improve our understanding of genes and health.  So taking part in the Generation Study also means that you might help uncover some life-changing early treatments for babies in the future. And finally, something that's super important to us is that people from Black, Asian and other minority ethnic communities have historically been underrepresented in this type of research. So, we're working hard to make the Generation Study as inclusive as possible to help genetic testing and treatments be improved for everybody in the future. So, there's many reasons to take part in the Generation Study.   Naimah: You mentioned the word altruistic there. Can you tell me what that means?   Mathilde: Yeah, so that's really to help society. They may not get benefits within their own lives or within their own family, but somebody somewhere will benefit from it in the future. And that's what altruistic means.   Naimah: Thank you. So, some parents might also ask, will this test tell me every illness that my baby might have now and in the future?  Mathilde: No. So first of all, we're still learning a lot about how genes work, how the environment affects them, and there's also many conditions that we still don't understand very well. So those are not in. Of the conditions that we do understand quite well. We did a big piece of public engagement in 2022 to try and decide which ones to include as part of the screening.  And while some parents told us that they would want to know every single thing in advance, a lot of parents were worried about how much it would raise their anxiety to find out about a potentially incurable condition at such a fragile and beautiful moment when you have a new baby. So, for this reason and many other reasons, we've decided to proceed really cautiously so that the conditions that we'll be testing for have been chosen to reflect 4 key principles. And you can find them on the website. But the main gist is that we'll only be looking for conditions that normally start in childhood, first few years of life. So, nothing around Alzheimer’s, nothing around breast cancer, for instance. And another principle is that there's has to be already existing pathways within the NHS so that the babies can be seen and treated quickly. So, we're only including those conditions that start in childhood, and something can be done about them early on.  Naimah: You can also listen to our podcast on our website 'Which conditions will we look for initially in the Generation study?’ to find out more about the list of 200 conditions, which we'll look for in the study and how this may change over the course of time as new evidence emerges.  So, another common theme with the parents was that they are aware that the NHS is already under a lot of pressure, and they asked if my baby is flagged for more testing, will I really be able to get the support I need from the NHS in time?   Mathilde: Yeah, that's a question that we've heard a lot actually, and it really makes sense considering the media coverage that's coming out daily, and that's been really in the papers for months now about how stretched the NHS is.  We've worked really closely with the NHS to ensure that all the babies that have a condition suspected as part of the Generation Study can be seen as soon as possible. So, our team has been in touch with specialists from across the country to understand how ready they are to take in those babies, to run confirmatory tests and potentially start treating them sooner.  So, it's been really key for us to make sure that we're not flagging up a baby for more testing and they just have to wait for months before they can get extra tests and attention. And that's so important for us to get right. In the long term, we hope that screening could actually relieve some pressure from the NHS if we can get babies to the correct doctor earlier on while their health is still good.  Naimah: Some parents might also ask, this research sounds very new. Is my baby going to be a Guinea pig?   Mathilde: Those two words, Guinea pig, came up again and again in almost every single session that I've had with parents, it was almost a freaky coincidence. I find that most parents use this wording to mean, will we inject anything into their baby or give them any medication that has not been tested and approved?  And the answer to this is no. What does happen is that when a baby's born after the birth, we need to take a few drops of blood so that we can create their genome, their DNA, and normally we'll take a bit from their umbilical cords, and that is happening in most of the birth at the moment of the participants.  But if for any reason we couldn't take that, maybe it was a complex labour, there was some emergency. The parents are asked a bit later if they would allow for a bit of blood to be collected using the heel prick methods. And that's a method that's been used in the babies in the UK within 5 days of birth for many, many years. And it looks for 9 conditions, as a current NHS test. So that's definitely safe. And usually when parents find out that that's all there is to it, they feel a lot more comfortable. A little disclaimer here because we mentioned the 5-day heel prick, while we use a similar method to get the blood, if w

In this explainer episode, we’ve asked Callum Morris, Pharmaceutical Research and Development Insights Manager at Genomics England, to explain what happens in a clinical trial. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel. If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What happens in a clinical trial? I'm joined with Callum Morris, Pharmaceutical Research and Development Insights Manager for Genomics England, to find out more. So, Callum, first things first. What is a clinical trial?   Callum: So, a clinical trial is a study that looks to people to answer a specific medical research question.  So, this involves gathering a group of participants that are willing to participate in providing evidence on how to improve clinical care. And so, the main purpose for a clinical trial is to evaluate health related outcomes between different groups of participants. If it's an interventional clinical trial, you change clinical care for one group and not another.  And evaluate whether the change you made improved health outcomes for that group, or if it's an observational clinical trial, you might focus on different groups but not change anything about their clinical care and collect real world data to understand how outcomes differ across the groups.  Florence: Can you briefly explain what we mean by real world data?   Callum: Sure. So real world data relates to data collected routinely as part of standard clinical care. So, it could be collected from your electronic health records, data from product or disease registries, or data gathered from other sources such as digital health technologies.  And all of this can inform on particular groups from the population you're interested in.  Florence: And are there different types of clinical trials?   Callum: Yes. Clinical trials can take many forms depending on the medical research question you're trying to answer. They could be related to understanding the risk of disease. So, evaluating a potential risk factor that you may be concerned with. They might evaluate preventing disease. So, what different approaches can you take to people who have never had the disease, and does this prevent its occurrence? You can have a clinical trial that looks at screening for disease. For cancer, that's really important.  Does a new screening approach mean more people with cancer can be identified earlier? And importantly, does this lead to an improvement in survival? You can have clinical trials that evaluate the different approaches to diagnosing a disease and can you diagnose a patient earlier and better?  And then the classical clinical trial is revolving therapeutics or different treatments, and you can have treatments that are addressing the disease itself. Or you'd have treatments that are controlling the symptoms of side effects you might get from another treatment you might be taking.   So even within a specific medical research question, you can have different clinical trials depending on how much evidence you already have regarding that question. For clinical trials involving the assessment of new treatments and therapies, these are broken down into three stages and we call these phases.  So, you have phase one, phase 2, and phase 3.  Florence: Can you explain a bit more about these phases?   Callum: Sure. So, the overarching medical research question might be, what is the safety profile of this new therapy, and does it work improving on the current standard of care? So, you'll break this down depending on the phase, and with each phase you expand your clinical trial to a larger population.  Phase ones are typically on a small group of people around, let's say 20 to 50, and are designed to check the safety of a new drug that's being entered into humans for the first time. Sometimes, especially in early phase cancer trials, you're trying to find the right dose for your patients.  So, you might take a small group, test them on a low dose, and if there are no severe reactions to the new drug, you start incrementally increasing your dose a little bit more. And this gives you a really good idea of the safety profile of your drug as you try it for the first time in a human population.  Next, you'll move on to a phase 2. And these are typically larger than your phase one, around 50 to 200 people. And, usually you use the dose recommended by the phase one. So instead of slowly adjusting your dose and just focusing on the drug safety profile, the phase 2 will evaluate the safety of the medicine in a large population, but also have an additional focus on health-related outcomes.  Is the medicine causing the effect you want? Whether that's relief of symptoms or for cancer reduction in the size of your cancer. If the data is really promising from your phase two, it will move to a phase 3. And the idea is the same, increasing the size of the population. typically phase threes can be from 300 to 3000 participants.  And the key thing here is that you will evaluate the potential benefit of your new treatment against the current standard of care. Normally, meaning the treatments that are already available in the clinic. Health regulators will need to look at all the data collected from all the trials before they approve it for the general population.  And typically, they need a phase 3 to do this. They need a phase 3 to confirm that the benefit provided by the treatment outweighs the potential risks associated with it, across a fairly large cohort of participants. And this is to ensure the therapy is appropriate to be given to the general patient population.  But also, a phase 3 is needed to see that if the new treatment is moving clinical care forward in the right direction and in providing improvements for patients against what is already available in the clinic. And this is the process by which we call it evidence-based changes, to make improvements to clinical care.  Florence: So then how do people join clinical trials?  Callum: So firstly, it's about becoming aware of the clinical trial. You might be referred to a clinical trial by your doctor who's been aware of it and where it is. Or you might be able to find a clinical trial using clinical trial databases or finding about them through patient advocacy groups.  And they should be able to tell you which hospitals are taking part in the clinical trial. So, the next step might be your doctor can contact someone on the research team, and there is always a principal investigator per research site that is always a medical professional.  The study team at the site have all undergone training from the people organising the trial to run through the protocols necessary to keep the trial consistent in different sites.  Once they've been contacted, you'll undergo a screening process, and what they'll determine is your eligibility for the trial. They might assess medical history or your health status. And if you're eligible for the trial, the next step is to provide informed consent. The healthcare team should provide detailed information about the trial, its risks and benefits, the aim of the trial, and who's funding it.  And what are the treatment options for participating and not participating in the trial? How long is the follow-up in the clinical trial? And what will happen if you leave the clinical trial? And then also what are the safety concerns for the clinical trials and the possible side effects if it's something to do with a new treatment. Once you've been informed of all these details and you agree to be part of the clinical trial, you'll sign a consent form, and that means you're officially enrolled in the clinical trial.  Florence: And what happens once someone is enrolled in a clinical trial?   Callum: Once you are in the trial, you'll follow the procedures outlined in the trial protocol. This can take many forms, but normally it involves more regular follow-ups and check-ins with the clinical care team. And this is to establish safety concerns and to enable lots of data collection.  There also may be additional checks related to health outcomes during the trial, and so the study team may want to take additional samples to understand what is happening physiologically during the study. There also may be additional questionnaires for you to fill out, to capture patient reported health outcomes.  And this is to understand the patient's quality of life whilst they're on the trial. So, depending on the protocol, you may be followed up for a set period of time, and that may get less frequent as time goes on. And of course, you may pull out of the trial at any point after which the follow up will stop.  So, following data collection, there may be a while before you see anything, but results should be published following analysis of the data.   Florence: And finally, why might someone want to be involved in a clinical trial?   Callum: Clinical trials are all about providing evidence to improve clinical care. At any time we want to make a change to healthcare, we want it to be evidence-based. And so, this requires lots of people all contributing in a group effort to generate a data set large enough to determine how to change our approach to healthcare and move the field forward for improving people's lives.  Florence: That was Callum Morris explaining what happens in a clinical trial. If you'd like to hear more explainer episodes like this, you can find them on our website www.genomicsengland.co.uk. Thank you for listening.