Behind the Genes

Dr Harriet Etheredge, Gordon Bedford, Suzalee Blair-Gordon and Suzannah Kinsella: How do people feel about using genomic data to guide health across a lifetime?

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: Thank you so much, Suzalee. And I think it’s just wonderful to hear about the personal impacts that this kind of work can have and thank you for bringing that to us.  Gordon, I’ll hand over to you. I’d be really interested in your thoughts on this.

Gordon: So my role in the Public Standing Group was to give my section of society my experiences in life to bring them together with other people, so experiences like Suzalee and the 24 other people that joined us on the study, to bring our opinions together, to bring our wide knowledge and group experiences of life. And it’s important to have a wide group, because it forces us to wrestle with differences of opinion. Not everybody thinks like I do.  As a pharmacist, I can see the practical side of genomics, like pharmacogenomics, where we could use a baby’s genome to predict how they’ll respond to drugs over their lifetime. That’s a game-changer for avoiding adverse reactions or ineffective treatments, but not everybody’s sold on it.

Some in our group worried about privacy, who gets this data, or ethics, like whether it’s fair to sequence a baby who can’t say yes or no. I get that. I don’t have children, but I hear those things clearly. The most interesting bits for me, the pharmacogenomics discussion in meeting two stood out, everyone could see the tangible benefits of tailoring medicines to a person’s genome, making treatments more effective, and in Meeting 5 designing our own lifetime genome resource was also fascinating. Ideas like it for public health research showed how far-reaching this could be. Some of the challenging sides of things that I came across, the toughest part was grappling with unknowns in Meeting 4, like how to share genetic info with your family without damaging relationships. Those risks felt real, and it was hard to balance them against the benefits, especially when trust from groups like minority ethnic communities is at stake.

Harriet: Thank you so much, Gordon. I think from you and Suzalee it’s so fascinating to hear how you were grappling, I think, with some of your personal and professional feelings about this and your deeply-held personal views and bringing those first of all out into the open, which is something that is very brave and we really respect and admire you doing that, and also then understanding that people do hold very different views about these issues. And that’s why bring these issues to an engagement forum because it’s important for us to hear those views and to really understand how people are considering these really tricky ethical issues.

So, Suzalee, I’m wondering from your perspective how do you feel we can really be respectful towards other people’s points of view?

Suzalee: Yes, Harriet. In spite of the fact that we had different viewpoints on some topics discussed, every member, researcher, presenter and guests were respectful of each other’s point of view. We all listened to each other with keen eyes, or sometime squinted eyes, with a hand on the chin which showed that what was being said was being processed or interpreted. All our views were recorded by our researchers for further discussion and analysis, therefore I felt heard, and I believe we all felt heard. 

Harriet: Do you have any examples that you can recall from the groups where there were differing points of view and how we navigated those?

Gordon: Where we had screening at age 5, but we agreed on an opt-out model, because it could help spot issues early. But some worried - psychological impacts, knowing too much too soon. But we looked at an opt-out model rather than an opt-in model because it’s easier to say to somebody, “If you don’t want to continue with this, opt out” rather than trying to get everybody opting in at every different age range. So, as we reach the age of 5, 10, 15, 20, whatever, it’s easier to get people to opt out if they no longer want to be part of that rather than trying to get them to opt in at each stage throughout their life.

Harriet: Suzannah, do you have anything to add there as a facilitator? How did you feel about bringing these different points of view together?

Suzannah: Yeah, you asked about where are the tensions, where do people maybe agree a bit less or agree and hold different views, and I think what stands out is particularly…  There was an idea floated by one of the speakers about you could have your DNA data on an NHS app and then, let’s say if you’re in an emergency, a paramedic could have access to it or others. And that really I think brought out quite a wide range of perspectives of some in the group feeling, “You know what, anyone who has an interest, anyone that can help my health, let them have access to it as and when, completely fine,” and others took a more cautious approach saying, “This is my DNA, this is who I am, this is unique to me, my goodness, if someone, some rogue agent manages to crash the system and get hold if it goodness knows what nightmare scenario it could result in,” and so had a much more keep it locked down, keep it very limited approach to having access to your lifetime genome data and so on. So that was a really interesting example of people going, “Yep, make it free” and others going, “No, just for very specific NHS roles,” which I thought was fascinating.

Harriet: Yeah, thank you so much, Suzannah. And I think it’s a real tangible challenge that those of us working in this area are trying to grapple with, is finding the middle ground here with all of the challenges that this involves, for instance, our data infrastructure and the locations at which data are held.

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Harriet: I think this brings us really nicely onto looking at some of the ethical, legal and social issues that we need to think through when we’re considering the lifetime genome.  I’m wondering if we can expand on some of these and the importance of addressing them. Gordon, would you like to give us your thoughts?

Gordon: Sure, thank you. Our job was to dig into how a baby’s genome could be used over the lifetime, think pharmacogenetics for better drugs, early childhood screening for conditions or carrier testing to inform family planning. We saw huge potential for individual health like catching diseases early, but also broader impacts like reducing NHS costs through prevention. Weighing the risks and benefits. The benefits like earlier diagnosis or research breakthroughs grew clearer over time with ratings rising from 4.1 to 4.7 - that’s out of, I believe, a figure of 5, but risks like data breaches and family tensions over shared genetics stayed significant. We agreed the benefits could outweigh the risks but only with mitigations like transparent governance and strong security. And what are the global implications moving forward? What we discussed isn’t just for the UK, it’s feeding into the global conversation about newborns in genomic research. That responsibility made us think hard about equity, access, and how to build public trust.

Harriet: Thank you, Gordon, I think there’s so much there to unpack. And one point I think in particular that you’ve mentioned, and this came out really strongly as one of our main findings from these groups, was the way that a lifetime genome and the way that we might deliver that information could really impact family dynamics in ways that we might not have really thought of before or in ways that we really have to unpack further. And, Suzalee, I’d love to hear from you about this, how might diverse family dynamics need to be considered?

Suzalee: Harriet, as it relates to diverse family dynamics a burning legal issue, which is then triangulated into being considered an ethical issue as well as a social issue, was the question can siblings of sperm donors be informed of life-threatening genomic discoveries? Whose responsibility is it? Will policies now have to be changed or implemented by donor banks to take into consideration the possibility of families being part of the new genomes programme?

Harriet: Yeah, thank you, Suzalee. I think there’s so much there that we have to unpack and in the Generation Study we’re starting to look at some of those questions, but going forward into potential risks, benefits and uses of the lifetime genome, all of these new technologies around human reproduction are things that we’re going to have to consider really, really carefully through an ethical and legal lens. Suzannah, I wondered if you have anything to add to these as major ethical issues that came out in these groups.

Suzannah: I think, as you say, people were so fascinated by the idea of this information landing in a family, and where do you stop? Do you stop at your siblings, your direct family, the brothers and sisters of a child?  Do you go to the cousins?  Do you go to the second cousins?  It’s this idea of where does family stop. And then people were really interested in thinking about who does the telling, whose job is it? And we had this fascinating conversation – I think it was in Workshop 3 – where this very stark fact was shared, which is the NHS doesn’t know who your mother or your father or your siblings are; your NHS records are not linked in that way.

And so that presented people with this challenge or concern that “Actually, if I get quite a serious genetic condition diagnosed in my family whose job is it to share that information, what support is there to do that and how far do we go?”  So, I think people were really fascinated and hopeful that Genomics England will really be at the vanguard of saying, “How do we as we move into an era of more genetic data being used in our healthcare, how’s that managed and how’s it shared?”

Harriet: Yeah, thank you so much, Suzannah. So I think that what’s coming out through everything that you’re all saying is the huge breadth of issues that came up here. And of course we’re seeing, very encouragingly, so many nods to the potential benefits, especially around things like pharmacogenomics, but we are seeing some risks.  Gordon, I wondered if you’d like to elaborate a bit further.

Gordon: So, something that came up, and it divided the group quite considerably, carrier status divided us. Some saw it as reducing disease prevalence and others feared it could fuel anxiety or stigma amongst the family or other families. It showed how personal these choices are and why families need control over what they learn.

Harriet: Yeah, it’s a very good point, and carrier status is something that could be a conceivable use of our lifetime genome record. Suzannah?

Suzannah: Just building off what Gordon was talking about, I remember there were also discussions around are we getting into a state where this is about eradication of so many different conditions, and actually how does that sit with a society that is more embracing, accommodating and supportive of people with different health needs. So, I think that was quite a big ethical discussion that was had, is, and particularly where we think about what we screen for in the future over time and so forth, people really being conscious that “Actually, where are we going with this? Are we risking demonising certain conditions and saying we don’t want them on the planet anymore and what are the consequences of that?”

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Harriet: And I think came to a point in our final meeting where we were asking our participants, so Suzalee and Gordon and everybody else in the room, whether you might consider having a lifetime genome for yourself and what that would look like. We’d love to share your views about that, and Suzalee, I’m wondering if you can share your thoughts on that with us first.

Suzalee: Definitely. I would wholeheartedly be interested in the lifetime genome programme if it was offered to me right now. I believe that the pros for me are phenomenal. 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: Thank you, Suzalee. And, Gordon, how did you feel about it?

Gordon: Being part of the group showed me how genomics is both thrilling and daunting.  I’d lean towards ‘yes’ for a lifetime genome resource for the chance to detect conditions early, but I get why some people may say ‘no’ over the data fears or ethical lines. 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. Laws would have to be enacted regarding the storage, use and availability of genetic data. We haven’t yet seen as well, how AI’s complete benefits in medicine will develop over time.

Harriet: Thank you so much, Gordon and Suzalee, for sharing that. And, Suzannah, I know that at the end of the Public Standing Group we generally asked all of our participants whether they would choose to have a lifetime genome, the same sort of question I’ve just asked Suzalee and Gordon. I wondered if you could just briefly give us an overall sense of how the Public Standing Group participants felt about that.

Suzannah: Yes, so it’s interesting to see that actually not everyone said, despite spending a year or almost a year discussing this, not everyone said, “Sign me up,” 6 said, “No” or “Maybe.” And the reasons they gave, this idea, “Well, all this data, could a government sell it off?  What guarantees have we got?”  So that was a reason. Somewhat of a concern also about breaches but also this idea of “What do I really want to know? Do I want to have a lifetime resource that can tell me what’s going to happen next in my health?” and some say, “Let me deal with it when the symptoms start coming and that’s the way I want to handle it.”  So, yeah, about 20 said, “I’d be really interested,” similar to Suzalee and Gordon, 6 on the fence or firmly, “No thanks.”

Harriet: Thank you so much, Suzannah. I think your point about uncertainty there is so relevant and important to us. We see uncertainty across genomics and we’re layering that here with uncertainty about futures, we’re layering that with uncertainty about health. And I hope that this has served to really illustrate the magnitude of the challenge we’re looking at here and I think also why for us as Genomics England this is just something we’re exploring. There’s so much to unpack, there’s so much still to be done.

In terms of our next steps for Genomics England, it feels like we could speak about this for a week but I’m going to have to wrap it up here. So, for us what are our next steps?  We hope really that as we publicise the findings of this Public Standing Group and when we start combining some of our work and looking at it in harmonisation with the work that others are doing across the world, we might be better positioned to understand the potential future directions that a lifetime genome could take.

That’s obviously very, very exciting because we expect to see this area of enquiry expanding significantly over the coming years.  And we’re already hearing about a number of other countries who are also doing birth cohort studies like we are who might hope to use similar applications of the lifetime genome going forward. So, there’s a real opportunity for us here to collaborate and it’s really heart-warming that the voices of our participants in this Public Standing Group can be used to facilitate that level of engagement. For us at the Generation Study, we’re already looking at the next iteration of our lifetime genomes work and we’re being led by the findings of this Public Standing Group as we move forward, specifically in that we’re going to be starting to take some of these emerging themes to the parents of our Generation Study babies to really find out how they would feel about them.

Harriet: I’d like to extend my sincere gratitude to all for being my guests today, Suzannah Kinsella, Suzalee Blair and Gordon Bedford. Thank you so much for your time and joining me in this discussion of the lifetime genome. If you’d like to hear more content like this, which I am sure you would, please subscribe to Behind the Genes on your favourite podcast app. Thank you so much for listening. I’ve been your host, Dr Harriet Etheredge.  This podcast was edited by Bill Griffin at Ventoux Digital and produced by Deanna Barac for Genomics England.

Dr Natalie Banner, Paul Arvidson, Dr Rich Gorman and Professor Bobbie Farsides: How can we enable ethical and inclusive research to thrive?

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 you always feel like you’re doing that as a parent as well to see if what you’re doing is, you know, if you’re still communicating while you’re trying to be a parent. 

Natalie: Fantastic. Thank you so much for sharing that with us, Paul, both the poem and also your exploration of how you got to that point in writing that poem.  Tremendously powerful to kind of understand and hear about that experience.  Bobbie, if I can come to you. Paul referred to that project as kind of audacious, can you tell us a little bit about the origins of the Helix of Love but also why storytelling, especially through poetry, was so important for the EPPiGen Project? 

Bobbie: Yes, of course, Natalie. But can I start by saying I was so pleased that you got Paul to speak for a while after because I always have to compose myself after hearing these poems because they really do hit so powerfully, however many times you hear them. And I think that is part of what we wanted to achieve with this project, we wanted to use innovative research methods, we wanted to be…  I love the word ‘audacious’; I’m going to borrow that.  We wanted to be audacious; we wanted to be courageous, and let me tell you, our Ethics Committee were a little bit worried about the sorts of things we told them we wanted to do. But we knew because we live and work in Brighton that the world is full of creative people and we’d already had such wonderful partnerships with people over the years, we knew that we could draw people into this project who would help us to work with this fabulous group of parents ,in a way that would give them, as Paul says, an opportunity to explore their own feelings and their own experience and share it as they wished.   

In an earlier conversation with Paul, which he might find surprising that it’s stuck with me so much, he used the word ‘extractive’ and he said that he’d 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, and the poetry project probably wouldn’t have come about if it hadn’t been for the passion of one of our participants who was sort of finding a love for poetry herself and said, “Can we try this next?” So, you know, it means so much to Rich and I that we ended up with this amazing book, but it’s not our book, it’s our poets’, as we like to refer to them, book.  

So, one of the things that we are so pleased about in this project is that 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. And I think another wonderful upshot from this project has been how receptive people have been to the work. And it’s a sort of commonly held myth that your average philosophy article has a readership of 3.4 people. Rich created a wonderful map to show how Helix has travelled round the world and touched thousands of people – I don’t think that’s an exaggeration – and we couldn’t be more grateful for that as researchers because we feel as passionately about these subjects as our participants and it is they who have really got this project on the map. Paul, you were going to come in, I hope. 

Paul: I feel like the one thing that this project really did was, I know PPIE is a phrase that’s bandied round but this project kind of stripped that theme apart and took the ‘I’ bit, this project is like built around inclusion and because it felt like, if we’d have just been jumping in a room with Dawn and told to get on with it, I don’t think it would’ve worked as well. The idea that it was kind of curated by Bobbie and Rich, we very much felt like our hands were held through the process, and after them having had to kick down doors in the Ethics Department to be able to get the project through at all, it’s like “What are you going to do to these poor parents?” having gone through that process themselves behind the scenes, then to kind of feel like we were guided through this process. And we were guided and held, and they were super-aware of all of us. And the fact that every time you tell these stories as a parent who’s gone through them there’s a cost. And we’ve had this discussion with the panel before and the communication group, about the fact that every time you come to a parent and say, “Tell us your story” there’s a cost.  

And so, they were aware of that, and they held that in both of their hands and so it couldn’t have been anything other than this collaborative project by the time we’d finished. 

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Natalie: We’re going to hear a clip from Lisa Beaton, a member of the participant panel at Genomics England, who shares what it has meant for her to take part in the project. 

Lisa: It was an amazing opportunity. I had a huge sense of imposter syndrome actually when I as invited to join, because I was aware of some of the people who’d already taken part in the project and although I can bring lived experience to the table I don’t really consider myself as a creative writer or anything like that, although I do enjoy it. When I first started in the group, we were just doing free-flowing writing. It was really cathartic, and I didn’t expect that in any way, shape or form. To put pen to paper without necessarily having any strategy in mind, just letting the thoughts come out and ramble away, I didn’t really know what was going to come blurting out onto my notepad, and reading some of it back was moving but it was frustrating. It was moving, it was everything really, that opportunity just as a safe space, knowing I didn’t have to share it with anybody if I didn’t want to but I could, and I could just, I suppose I would call it almost like a brain fart, it just rambled away and maybe it was a way of downloading some of the emotions that I was carrying.  

As the project went on and we explored different creative mediums I really enjoyed that and found different skills that I wouldn’t have thought about. And it was very thought-provoking, being able to go back and think about some of our very early experiences, which is, not that I’ve buried them but it’s just you move on to deal with the here and now, and it brought me back to some of those very raw emotions of the first days which I think are, I hope, helpful to certainly the medical community in terms of thinking about how they talk to new parents going through similar situations. I was very grateful. 

Natalie: Rich, I’d like to come to you now. As Bobbie and Paul have both mentioned, the outputs for this project have really spread far and wide and maybe beyond the kind of academic circles that you might typically think. I’d really like to hear from you about how you think the project has helped healthcare professionals, particularly really enabling them to understand a little bit more about what it means to be part of a genomic healthcare service and the journey that patients and families go through. Would you share a little bit about your experience in the project, particularly for healthcare professionals? 

Rich: Yeah, I mean, that was one of the things that when Bobbie and I set out to do this, that was one of the real aims, was to sort of help healthcare professionals have a bit more of an insight into what it means to access genomic medicine services from a patient or family perspective. And, as Bobbie said, there were 2 ways we could have gone and done this; we could’ve done some sort of conventional social science interviews, written that up in a lovely social science or philosophy journal article and no one would’ve probably read it, but instead we thought about the power of the arts to actually change in terms of how we were sort of collecting and collating people’s stories and then how we were sharing and disseminating those stories as well. And I think the medium by which stories are told affect the kind of stories that get told, as Paul was sort of hinting at earlier.   

When we ask patients to tell us their story, you know, there’s a level of expectation there about what people are being asked to say in a form in a way, and certainly we didn’t get people in a room and say, “You must write about genomics.” So many of the poems in the collection aren’t really about sequencing or big data, they’re about these kind of much wider themes of everyday life. And I think that’s been really powerful in allowing healthcare professionals to sort of understand for patients obviously genomics is really important but it’s not the be all and end all of everything that’s going on in their lives, you know, there are so many other pressures, so many other hopes and desires, and people want an opportunity to express some of those positive aspects of their life with their loved ones and it not just be medicalised all of the time.   

Again, as Bobbie said, it’s also opened up our research travelling really well and just become something that’s really accessible for people to pick up and read through, and I’ve had conversations with healthcare professionals that have said, “Oh I read through the book of poetry and it’s made me realise all of these things.” Language particularly has been a really prominent theme that people have reported, telling us they’ve learnt a lot about it, and thinking about how they write their letters and how they communicate with people. And obviously this isn’t new, you know, bioethicists for years have been talking about the need to communicate very carefully, very precisely and in a caring way, but I think there’s something about communicating those messages through a really powerful art form like poetry through patients’ own words that allows clinicians and healthcare professionals to sort of really get the impact of that in a very, very powerful way. 

Natalie: Thanks, Rich, really helpful insights there. I really want to pick up on your point about language and come back to Paul on that because I know that’s a topic area that can often be, you know, hugely sensitive to families that the medicalisation, the terminology that’s used, especially, you know, complex areas like genomics, coming back to this term we mentioned earlier about being sort of alienating. How have you found that the work through the EpiGen project and Helix of Love, has it potentially helped the way that families can think about the right sorts of language and enable health professionals to sort of approach some of these questions in a slightly more human way?

Paul: Difficult to say. It’s a very, very live topic all the time. There’s like a backchat communications channel with the Genomics England panel where, because we all go along and do this thing, but we all share that genomics common thread in our lives. One parent was breaking their heart about the fact that they’d had sight of genetic science reports that basically described their child, and children like them as ‘lumped together’ in a project, and she was gutted about it. And we all were as well, and we were all open-mouthed about it. The whole idea of kind of separating the science and the science language out from the people who are involved, it is our job, isn’t it, you know, our job as the panel members is to remind people that those are people, not statistics. But it’s a really live subject and the more people, the more professionals who can be reminded of that on a daily basis and the more we can find kind and open ways to deliver that message to professionals, and every single day that we do that makes a difference, I think. If one parent has to get less of a letter like that or one professional thinks more carefully about how they phrase stuff before it goes out the door, then that’s one less parent who’s got to go through that. 

Natalie: Absolutely. And I’m thinking about that insight. I suppose the anticipation and the realisation to healthcare professionals about the impact of the way they approach things, the language they use, the kind of mindset they might adopt with parents and families, one really important aspect of the project was to do sort of preparedness and the idea that you should be able to anticipate and plan for and acknowledge some of the ethical challenges that might come through when you’re dealing with questions of genomic healthcare where there may be lots of uncertainty, there may be a long journey to go through.  

Bobbie, can I come to you to help us unpack this notion of ethical preparedness as a core theme for EPPiGen? Help us understand what that means in kind of simple terms and why does it matter for those who are working in the genomic medicine and healthcare space. 

Bobbie: I think the way in which most people will have heard of this concept of preparedness is in relation to disaster planning. We know that some of the good things we try and do in life are also potentially fraught with challenges and difficulties just because of their complexity and because of the wide range of people and organisations that will be involved. Can we take this idea of preparedness and almost say, “You have a moral responsibility to be ethically prepared when, for example, you embark upon a really dramatic change in healthcare delivery or an introduction of fantastic new healthcare innovation”?   

And genomics seemed to be the perfect case study for this. We then had to say, “What does that actually mean in practice?” And I think here we wanted to move away from the idea that you can ethically prepare people by putting a small albeit very expert and clever group of people in a room to write guidance and regulations, those things are needed and they’re useful. But it’s actually much more important to almost recruit everybody, to bring everybody up to speed, so that the ethical challenges aren’t a complete shock to those who are delivering the service in the frontline, so that those who plan systems actually think whilst doing so of the ethical challenges that can be posed by the tasks they’re attempting to achieve.   

And I was a sort of founder member of the Ethics Advisory Committee at Genomics England, and it was so interesting in those early days because there were no patients, there were no participants. We were sitting alongside people whilst they designed and put in place basic processes, strategies and ethics was a part of that. And a really important part of that to me, at those meetings, was hearing what the potential participants had to say about it because, again, the Participant Panel was involved. And I found that those were my people, those were the people who were worrying about, concerned about the same things as I was. 

So, I think to be prepared we have to take on the responsibility of giving people who work in ethically challenging areas opportunities to come together to acknowledge the complexity of the task, to share strategies and tools, but also, very importantly, to not become divorced from the people that they are attempting to serve, because in fact we feel that this part of our project, and our project is much bigger than this and we’ve done some fantastic things working with healthcare professionals, medical scientists, etc, etc, but this part of the project is an attempt to say, “We can better prepare families as well by ensuring that we tell them that their voices are valuable, that they’re important, and they help rather than hinder healthcare professionals in doing their jobs.” 

Natalie: That’s a really important point around the idea that this approach can help, can be positive. Because I think sometimes you think about preparedness and, and quite often with ethics it’s about risk, it’s about, you know, “How do we avoid the risks?” but there’s a very positive story to tell about taking a more preparedness-type approach to thinking through ethical complexities, challenges and so on, both for health professionals and, as you say, for families. I wonder if you could just talk a little bit more about the kind of positive aspects that that can bring to everyone in that genomics healthcare journey, both the health professionals and the families.  Because I think sometimes it’s easy just to think that it’s mostly about sort of avoiding the risks and the pitfalls, and that might be harder to engage with people if you take that sort of risk-based approach. 

Bobbie: Yeah, it’s an interesting one. I think the ability to confront risk and uncertainty is a sign of maturity. And we find medical students, for example, hate any sense of uncertainty; they want to be told how to do something and they want to know that they’ll be able to do that thing and get it right. And our job is often to say, “Well it’s not going to be as easy as that, in fact it might be impossible, and here’s what you have to do instead and here’s how you allow yourself to fail or to not achieve in the way that you want but still do something really meaningful for the people that you’re caring for.” 

So, I think there’s that aspect of saying, “It’s part of medical education, it’s part of how we should think in organisations that wherever you take risks, wherever you try to push frontiers, blur boundaries…”  I mean, genomic medicine has done something really interesting in terms of blurring the boundary between scientific research and clinical care. Wherever you do these things there are going to be challenges but those challenges, they’re fascinating, they’re interesting, they can bring us together. If we’ve got a shared will to get through them, you know, to make things work, then it’s enlivens what you’re doing; it’s not a barrier.  

I sort of began teaching and working in the space of bioethics right back in the ‘80s, which is a shock to you, I’m sure, but in those days I’m afraid that ethics was seen as a block, a barrier, a hurdle that people had to get over or through. And I think there’s still a sensitivity, and certainly, I myself have been sort of challenged on critiques that I have offered to say, “Oh that’s a bit harsh.” But I think what ethics attempts to do now, and certainly through really putting a positive spin on this idea of working together to establish ethical preparedness in important spaces, is to show that actually ethics can be very facilitative, it can be very supportive, and it can help people. It’s not a surveillance mechanism, it’s actually another clinical tool and something that, you know, people should seek support around. 

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Natalie: Rich, if I could come to you thinking about that reframing, I suppose, in your own research practice as an early career researcher, whether you’re seeing that maturity in approach in thinking about some of these really complex, knotty ethical questions in genomics, are you seeing a greater appreciation for those?  And where do you think you’re going to take your research as a result of this project in that space? 

Rich: Yeah, thanks, that’s a great question. Yeah, I think so, and I think one of the things that’s really been revealing in this is the appetite for this kind of work in the sort of genomics sector, an appetite for thinking about the sort of complex ethical issues, for engaging with kind of arts-based research, for sort of finding new language and new spaces to involve patient and family perspectives and stories and think about how we can learn from them.   

I think in the highly scientific, highly technical space of genomics we often assume that everyone wants numbers and hard data but actually I think the way that this work has travelled, the amount of invitations we’ve had to sort of exhibit this work and talk to healthcare professionals and scientists about this work shows that there’s this really rich appetite for thinking about this complexity and doing that work of ethical preparedness, as Bobbie’s talked about, and I think it’s fascinating. And I know a lot of the participants who joined in our project have also sort of had opportunities from being involved in our work and found that there are people that want to listen to their voices and hear from them and learn from them as well. So that’s been really exciting, and I hope it will continue and I hope there’s opportunities for much more interdisciplinary collaboration in the genomics space with philosophers, with social scientists with ethicists, with artists and, importantly, with patients.   

Paul: You mentioned the idea that certainly the poetry at the very least has allowed those voices to get into different spaces, and I think when those things first started happening it was when we at least as the people who’d written the poems felt that there was a huge big impact from this stuff. And I wasn’t the first one to read one of these poems out loud, and in a way the collection of poetry became bigger than the sum of its parts in a funny kind of a way. And I can’t remember but somebody read one of the poems at a conference somewhere and they said at the end of it that you could’ve heard a pin drop, and it was just that thought that actually with a big audience expecting kind of quite dry subject matter about genetics, to have felt that moment where the poem got launched off the stage and then it impacted on the audience and then, the way they described it, you could almost kind of feel them describing the ripples of the poem just like spreading out amongst this kind of silent audience and everyone kind of taking this kind of mental sigh of like “Oh that’s what it feels like.” And the idea of that happening was when, for me anyway, when we knew that what we’d created was bigger than the sum of its parts and had its own legs, Bobbie and Rich had been the Dr Frankensteins of this kind of amazing, beautiful monster.

Natalie: Obviously the poetry’s got into your soul, Paul, the metaphors are fantastic. But just to make sure we bring in even more participant voices and perspectives into this we’re just going to hear now from Jo Wright, who’s another member of the participant panel, who’s going to share what the project and the participant in it has meant for her. 

Jo: So being part of the EPPiGen Project, it helped me to find my voice in an area that was relatively new to me, and also it was a way to take control of my own experiences rather than feel like I’m being swept along by a lot of systems.   

And there were things that I really value that I thought contributed to making the project so successful. One was that they asked the question “What is this experience like for you, the experience of being part of a research project, the 100,000 Genomes experience of waiting, the experience of having your data in the library?” And no one had asked that before. You go to your appointments and you’re in the system and, you know, it’s kind of, everyone was finding their way to some extent because it was new for all the clinicians as well, but the fact that they asked, because no one asked that before, I don’t have an outlet for that.    

And then the other thing was that it was completely open so there was no research interview or questionnaire to answer, no expectation about what it was going to look like at the end. And I think working that way really strengthened the connection between us as parents of children with rare conditions and then also our relationships with Bobbie and Rich as the researchers and with the wider clinical community when they started to see our work and respond to it. So it was a way to understand people’s individual experiences but it also made us feel connected and empowered through sort of like shared human experience, and that could be between us as the participants but also shared experiences between us and the researchers or us and clinicians and scientists that were looking at what we’ve done. 

Natalie: So we’ve heard lots about the experience of participating in this fantastic EPPiGen Project, the kind of creative storytelling methods, the audacious methods that have been used, and some fantastic impacts beyond the kind of typical what could be quite dry sort of academic circles that this kind of work has spread out to.  I’d be really interested to hear from each of you about the takeaways, what you’ve learned, what’s changed for you and what you’d like our listeners to really understand about this project and the work, and the sort of outputs from it and the ways it might continue to have resonance and impact going into the future, so whether people are patients, families, clinicians, researchers. What would you like people to remember and what’s affected you most about the project?   

Bobbie, I might start with you. 

Bobbie: I think we have to always be very careful when we get excited about something - and the ‘we’ here are the people in the health community, the education community, etc - to remember. As Rich said earlier, that this is only ever going to be quite a small part of other people’s lives. You know, we’ve all devoted big parts of our careers, our enthusiasm, to thinking about genomics, to working in this space. I would really like people to pick up the book and work to understand a bit better about the everyday lives, the hopes, the expectations, the fears of the families who may or may not get a diagnosis, may or may not get on a good treatment path, all of whom want the best for themselves and everybody else from this venture.   

But, as Paul knows better than most, it won’t come to everybody, and we don’t want anybody to be forgotten along the way. The people that signed up for Genomics England as participants were pioneers alongside medics and the scientists, and in these early years we want their experience to be recognised, and their experience goes much beyond their interaction with Genomics England and, unfortunately, all the work that we’ve produced shows how many challenges families have to face to secure a good life for their children, and I just want us all to just keep that in mind.   

Natalie: Incredibly important to maintain that focus, that awareness. And, as you say, Bobbie, there’s an interesting balance where there is a need for the drive and the innovation and the ambition to help ensure that we are pushing at the forefront of medical research but not leaving people behind and not ever forgetting, as you say, the experience of people who are actually at the forefront of this research and of genomic healthcare.  

Paul, could I ask for your perspectives on this, and particularly how you see patient voices being involved in the future of genomic medicine, especially in light of your experience in the EPPiGen Project? 

Paul: I think the biggest surprise and biggest takeaway for me was the project gave me, I mean, I can’t speak necessarily for all the other poets, but you only need the evidence in the book itself. They gave us the tools, 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. So it gave us a way to talk about all of those things and a way that was I suppose slightly removed to start with. 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.   

But, because you’ve got that tool and you’re used to using it or you’re familiar with using it, it then gives you that safety. That’s how I felt about it anyway, it was a massive tool to be able to get behind all of these things that I didn’t even know I was feeling, or I knew they were making me uncomfortable, but I didn’t know what they were or what name to give them. So the poetry gave us a chance to get behind all of that. Having read the poems, it feels like it’s that for everybody but obviously you’d have to speak to them to know, but it certainly felt like that for me. 

Natalie: And, Rich, your perspective.  What are you taking forward from the project, so what would your sort of key takeaway be? 

Rich: I think it shows what is possible under that PPIE acronym. And there are many ways to do that involvement and engagement, it doesn’t have to be a sort of dry tick-box exercise, there are much more creative ways to bring people’s lived experiences and perspectives into conversations with genomics. So really, I suppose it’s a call for other people to explore working in this way as well and think about what other kind of creative outputs could work here. I mean, we’ve had huge success, and I think a really interesting impact from working in this way.   

And certainly as an early career researcher it’s been really formative in my sort of academic journey, you know, reaffirmed that this is the kind of work that I want to do, working in this really co-productive way. And I think it’s possible, it can be done, and, you know, ultimately it’s just been a real privilege to do this kind of research, to sort of be trusted to sort of hold a space together for sharing people’s stories and give people a platform to share some really powerful profound stories. And going back to what Paul was saying earlier, I think he hit the nail on the head, as he very often does, this is about evoking people’s experiences, not just explaining people’s experiences, and allowing those stories to travel.  And we don’t know where stories will travel, we don’t know how stories will travel, we don’t know how stories will be received, but we know that they do sort of travel and they do have legacy and they stay memorable to people, they have emotional resonance. So, the impact of this work can often be hard to sort of pin down really specifically, but we know those stories are out there and people are listening and changing their practice as a result. 

Natalie: We’ll wrap up there. I’d like to thank our guests, Paul Arvidson, Professor Bobbie Farsides and Dr Rich Gorman, for joining me today as we discuss the EPPiGen Project. We heard some powerful insights from patients and families about their experiences, and why ethical preparedness is so important in the context of genomic medicine. If you would like to hear more like this, please subscribe to Behind the Genes on your favourite podcast app. Thank you for listening. I’ve been your host, Natalie Banner. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand. 

Vivienne Parry, Alice Tuff-Lacey, Dalia Kasperaviciute and Kerry Leeson Bevers: What can we learn from the Generation Study?

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 suffer from some conditions that we plan to identify through this study, and learn what some of their challenges are as well. You know, do they feel equipped to be able to support parents that are getting a diagnosis? As well as obviously their participants and the general public, to make sure that we’re aware of attitudes and perceptions as the study goes along.   

Vivienne: Because there’s always a danger with this kind of study that it’s people who are health literate who end up being involved. Whereas some of the people on whom the burden of rare disease is greatest may not either feel that they can access, or would want to access, this study. So, what are we doing there? How are we listening to people? 

Kerry: When we are looking at recruitment as well, like you say, you know this is a research study and when we look at history and when we look at participants in research studies, we very rarely do you get a diverse representation of people in these types of studies. So, it’s really important that those extra efforts are made really in terms of recruitment to get the right sample of people involved. And I know at Genomics England, that they have invested their time and money in terms of interpreters and translating materials and things, but actually it’s the sites and recruiting people that need to be well resourced in order to use recruitment strategies, because if we’re just looking at posters in waiting rooms, for instance, you’re going to get a particular demographic of people that will respond to those kind of posters, such as people who don’t speak English as a first language, it would be really difficult sometimes to read those kinds of posters and then to ask questions about that.  
 
We need skilled people within sites that are recruiting who have got cultural competence who can have those conversations, address some of those areas, some of those concerns so that we can get that diverse representation.   

Vivienne: So, there’s a whole piece about equity of access for everybody and Dalia, perhaps you can explain why this is so important, scientifically as well as ethically? There’s another piece about making sure that we get a full diversity represented.   

Dalia: We know that some of the conditions are more common in certain populations or certain communities. We also know that some of the conditions are caused by certain variants in one population but not in the others. And these genetic causes even of the same condition can vary between different communities and different genetic ancestors.  On the other hand, our knowledge about the conditions and the genes, and the variants which cause them, come a lot from what we’ve seen before. Where we’ve seen those variants in the patients with the disease, and importantly where we’ve seen those variants in control populations where these individuals which don’t have conditions.   
 
Therefore, if we lack the diversity in our datasets, we would not know about all the diverse reasons of why conditions can be caused, or how it progresses, or what it might mean for individuals. And we would not be able to have equitable testing, or we wouldn’t know whether the test works for everyone. If that happened, we might be in the territory where we can’t detect or don’t detect as well all the conditions across different individuals. But also, we may be having more false positive results and create more anxiety for families as well as burden for healthcare system.   

Vivienne: So, are you saying, Dalia, that actually sometimes we might get a false positive, or indeed a false negative, simply because in that person, the condition which we think is usually caused by a particular change, they’ve got a slightly different change and so therefore we’re not picking it up. 

Dalia: Indeed, but it’s one of the possibilities. If, let’s say, all our knowledge about certain genes came from a limited number of individuals, seeing a new variant in another individual might seem that it’s something really rare and never seen before and it’s potentially changes how the gene functions, we would say; “oh that’s maybe something which causes the disease,” when actually it can be that it is a benign variant, just a normal variation which is very common in another part of the world, it’s just that we don’t have enough data to know about it. So, we need to be aware of those risks and take it into account when we interpret the variants.   
 
And, we also need to be transparent when operating in the environment. There was historical and investment in the diversity in research and our data sets still are not as diverse as we would like to be. It’s shifting, the balance is definitely shifting in the last few years. A lot of effort is being done but the only way to shift the balance forever and make that genomic medicine work for everyone is to really actively engage those individuals and involve them in the research, and taking all the effort that Kerry was talking about.   

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Vivienne: Alice, that goes back to this thing about holding the genomic data, because you need to hold the genomic data because the thing about genomics as always, you need to know what happens next. So, for instance, if somebody had a negative result and then later developed a condition, you need to be able to go back that data in order to find out what the problem was. 

Kerry: That’s right. You know, as Dalia talked about, we know that there is a risk within the study and we try and be clear about that in our participant information that there are some babies where they may have a genetic condition that we will need not find it, and others where we might find something that doesn’t go on to be the actual condition. And we need to kind of monitor those in different ways.   
 
So in particular in the cases where, if we’ve returned a result where we don’t think we suspect a condition and a baby goes on to develop a condition, it’s quite complex how we monitor that, and we’re trying to go for a multi-track approach, and I think a lot of the benefits is some of the infrastructure that Genomic England already has that we can utilise.  So, some of the foundational things we’ve put into the study to help support the approach are things like the ability to contact parents regularly so we can actually work with them to find out over time if their babies develop conditions.   

As you say, ability and consent to access the clinical data about the baby so that we can then access national data sets, and then we can then potentially monitor to see if babies seem to be showing signs of developing a condition. And also, really continuing to work with a network of clinical specialists where we’ve work quite hard over the last couple of years to build that kind of network and engage with them about the study, because they’ll be the ones who the babies will come to if they develop those conditions. So, they are a really good route to us finding out, whether or not there are babies who have been part of the study who then go on to develop a condition.  
 
And I think the reality is that this is a really complex process and it’s something that even traditional screening programmes really struggle with, and that’s why this multi-pronged approach is really important, and why also we see that this approach will evolve over time, and at the moment, the important thing is we’ve worked hard to put the right foundations in to allow us to do this type of monitoring, and to really evolve that approach as things develop and as more things come along potentially where we can invest in.   

Vivienne: So, it’s interesting, isn’t it, because I guess that some parents would think that if you get a false positive or false negative, that it means that the test is at fault. And actually the accuracy of the test is good, but what we may have an issue with is that there is something else causing the problem that we don’t yet know about. So, a big part of this project is giving much, much more information about the causes of conditions.   

Alice: Yes, and I think that’s also why the discovery research aspect is really important, the fact that we consent for that ability to hold the baby’s data. So not only will we want to use it for the evaluation, but as I mentioned at the beginning, we have asked for parents to be able to allow us to link it to clinical data which then allows us to track over time and find out more information, because it’s always the quality of the information we know that will help us in the future to identify these conditions, so the more we can generate potential information, you know, the more we will learn as a society.   

And so it’s actually quite an altruistic thing we’re asking of parents, and that’s something we recognise and that’s why it’s also important we think about, how we continue to engage with the parents and the baby over their lifetime to remind them that we’re holding this data, but also to understand what their concerns and feelings are about us holding that data and how we’re using it for that broader research. 

Vivienne: And that’s very much what you’re involved in, isn’t it Kerry? 

Kerry: Yes, and I think sometimes in some ways that may offer some reassurance to parents as well, to know that’s there as a reference point if things do develop over time, but I know that one of the things we’re looking at as part of the evaluation, and the PPI Group we’re involved in, is looking at the experiences of patients through this journey because actually it will create quite a lot of uncertainty.   
 
As a parent of a child with a genetic condition, that uncertainty really is one of the hardest things to learn to live with. So at that early stage, one of the things we’re looking at is that experience, how much support people have received, whether that has an impact on the parent and their child and their on bonding and their experiences and things like that, and I think it is important that we do that, but I think also having those references, where you’re able to go back and ask those questions, that’s really important that the support is in place, and that pathway really for parents to know where to go to. Because sometimes, although we may arrange to have calls at regular intervals and things, sometimes the questions of parents don’t necessarily come at the time when they are having a telephone call. They come really late at night when there’s nobody to pick up the phone, so having as much information as we can available, and those support structures in place, is really key.   

Vivienne: We all start off these projects thinking that they are going to go in a particular way, but actually there’s a lot of flexibility in this study, isn’t there, Alice?  For instance, we will be looking at all those false positives, false negatives because we need to learn from that. We will be, perhaps, changing our approach as we go on if there is something that isn’t working out. Is that what we’re doing? 

Alice: Yes, I think what we have recognise is it is a study and therefore that involves learning by it’s very nature, and that’s why partly we’re working with external evaluation partners that Kerry’s involved with, but also why we invest in a lot of things internally. Like we do a lot of user research with our midwives and our participants, and also potential participants. Because, actually we don’t know the answer to this. No one’s done this before, and so this is about all of us really learning, and learning in the right way and continuing to do that throughout the study, but also more importantly capturing that information and making sure that at the end of it, we then have some understanding of if we were to see that it’s right to deliver this as a clinical service, what that might actually involve.   
 
But also, even if we get to that point, I think beyond that we will still continue to learn over time and that’s again why that long enduring consent is quite important, because we can then continue to maintain that long term evaluation and continue to maintain that long term potential to help further further research. And so that’s the thing where actually we’ll be learning for the next 10-15 years, really what the Generational Study has learnt, and actually what we have achieved through it. 

Vivienne: I just want to move back to something that you mentioned, Kerry, about conditions that we’re looking for, and there were a lot of very specific things. I’ve said that what parents wanted, but there’s also some scientific things, and Dalia might want to come in here, that these are conditions that we pretty sure that if you’ve got the particular genetic change, that you will get the condition – something called penetrance. So, you know, we’re not leaving people with a lot of uncertainty. But, how will we go about assessing new conditions as part of this study, or are we just on the ones that we’re on at the moment? 

Dalia: So, we started from the things we understand the best and we know how to detect them and we know how to confirm them because the tests that we are doing in Genomics England is a screening test, it will not be a definitive answer whether you have or you don’t have a condition. Anyone which will get a positive result will be referred to an NHS specialist clinician for further assessment. And some of those positive results turn out not to have the conditions and some of them will have, and they will have their treatment pathways. So, we’re started to very cautiously, and that’s what came from public dialogue, everyone was saying that; “you need to be really cautious, we need to see that it works for the conditions that we understand well”.  
 
But as a starting point, as we learn more, we’re learning of how could we expand that list.  What would be acceptable for public. Maybe some conditions will have an experimental treatment, which currently would not be included in screening but as treatments evolve, at some stages maybe there will be opportunities to include some conditions in the future.   
 
As our science evolves, we keep assessing the new conditions and seeing can we include them, would it be acceptable to parents, would it be acceptable to the healthcare system, and one of the things about screening it’s really important not to cause harm. There are a lot of benefits in screening but if we didn’t do it cautiously, it also has some risks, and we need to be very careful about it.   

Vivienne: Now Kerry, there are lots of parent groups who will come along to us and say; “oh you must include this condition,” but perhaps there isn’t yet a treatment, or there isn’t a pathway in the NHS that will help people get what they need. And I guess if we try to include too many conditions, we would actually undermine trust.   

Kerry: So, the patient organisation, our condition, Alström Syndrome, isn’t included in the list. For our condition, there is no specific treatment although we do have a highly specialised service, and it is very important to get early diagnosis because children can develop heart failure and there are symptom-specific treatments available there. But I get the reasoning why there needs to be a specific treatment and the need to include just a smaller group at the beginning, but our hope as with I’m sure a lot of other patient organisations, is that our condition will be added at a later time if it is found that this is something that would be acceptable in routine care.   

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Vivienne: Let me move on to another aspect of this study. These are babies, and we are holding their genomic information but at 16, they will be able to decide whether they want us to continue holding their genomic information. Alice, is that very much part of this programme to think about what we’re going to say and how we’re going to engage those 16-year-olds? 

Alice: Yes, it very much is. What I always say, because I get asked this question a lot, is that I don’t think we can pre-judge what that looks like. Because I look at my children, and certainly their lives are very different from my childhood, and I don’t think we can imagine exactly what our babies will look in 16 years and what that world looks like. I think the important thing is many of things we are trying to do is that we lay the right foundations in place, and part of that is ensuring that we continue to think about how we engage with young people as the study evolves and over time, so that we understand what the world is looking like from their perspective.   
 
But also, how do we equip the parents to talk about the fact that these babies are part of the study to them? What does that look like? How can we support them? And that’s very much something we want to be looking at in the next year, really working with parents from the Generation Study to understand how best we can do that so that they can have some of that conversation for themselves as well. I think we can’t pre-judge exactly how we need to talk about them and also not think it’s just one thing. We need to evolve and work with the children as they grow up, and work with their parents to equip them because, as I said, we don’t really know how they’re going to access information in the future. You know certainly TikTok didn’t exist when I was a child, and so that’s what we’ve got to think about is what’s the best avenues or forums to really engage properly with them as they grow. 

Vivienne: Kerry, what other concerns to parents have that we’re learning now?   

Kerry: I think the concern is that when treatments are being developed, that they are not necessarily being developed for the whole population. They’re often being developed for sub-sets of population because we don’t have a complete dataset. And when you think about people being involved in research, people feel that they are being left behind because their data is not necessarily represented within there, it doesn’t reflect their community, and it’s not being discussed within communities, the different research opportunities and things have been available, I think it’s the fact that we’re not investing enough in community engagement and dialogue to explain more about genetics.  

I think technology has advanced at pace. As a parent of a child with a genetic condition, that is very encouraging to see that, but I think sometimes the support and the information is not necessarily keeping up, so we’re not having those open conversations really about genetics and genomics, and I think that’s one of the things I hope that this study will really lead to, that it will now become much more part of everyday conversation.  

Because often, when you have a child with a genetic condition, you first hear about a condition, the way you take in that information and ask questions is very different than having a conversation with the general public about genetics. When you’re concerned that your child may have a condition or you may have a condition yourself, you’re in a completely different mindset. So, the hope is that that dialogue will open so that people will be able to ask questions to learn more about the projects and things that are out there and available so that people are included and can take part in research if they want to. But it’s important to remember that not everybody will want to. It’s about being given informed choices and to do that we need to make sure that the support and the information is appropriate, inclusive and accessible.   

Vivienne: 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.  

Kerry: I completely agree. I think it’s like you say, if people say no, that is completely their right to do so as long as they’re saying no when they’ve been given the information to be able to really take that on board, think through, consider it and then make an informed decision. I think often people say no because they’ve not been given the right information to be able to understand what is expected, so they’ve not necessarily been given the opportunity. And I think we all want good outcomes for everybody. That doesn’t mean delivering the services in the same way. Sometimes we need to deliver services in different ways because often services aren’t very accessible for some communities to be able to access. So sometimes we need to make changes, adapt, to make sure that everybody has the same opportunities to the same outcomes. 

Vivienne: We are constantly re-evaluating, rethinking, re-engaging to try and make it the best we can. Whether it’s with different communities and different approaches. Whether it’s with constantly assessing people who’ve had false positives, false negatives and finding out why that is the case. And in the future, I think this will have some really major effect.  Dalia, you’re the scientist amongst us today. Tell us what you’re hoping for from this study in science terms. 

Dalia: So, first of all, we want to find the babies which we can treat before we develop symptoms, before we get ill, so that we can have more fulfilling lives. That’s the bottom line. But we’re doing that, we also will learn about the conditions. We’ll learn a lot about the natural history of the conditions. What happens when you detect it before baby gets ill, then you start treatment, and how does it work in the diverse communities and diverse populations that we’ve talked about. Are there are any differences based on people’s ancestry, but not just ancestry, about their lifestyle, about anything else which can affect how disease develops, or how the care or treatment goes.   
 
So, that’s kind of the bottom line. The top line and now our ultimate aim, probably many years from now, would be that we can detect variants of genes or conditions before they develop, and we can create treatments for them before our children get their conditions.  That’s something that the science community is very excited about. I think we’re quite a few years from that, but that’s where we hope all this will be heading in the future.   

Vivienne: It’s really becoming a possibility, but the science is only the first part of it. It’s the human interaction. It’s the how it lands with people. It’s how they feel about it. It’s how they trust it. And these are all the things that we’re really working on at Genomics England to make this study not just a scientific success, not just a success for the NHS, but also something that is really meaningful and important and valuable and trusted for people having babies. Would you agree? 

Alice: Yes, 100%. I think, just to come in there, Viv, I think we’ve talked a bit about the importance of public trust and being the foundations of what we do, and I think that’s something that Genomics England’s always held true to itself, but I think for the purpose of the Generation Study, it’s been one of kind of the foundational principles from the beginning, and I think Kerry and you have touched upon some really important themes today about how it’s not a ‘one size fits all’ approach. And I think very much that piece that we touched on a bit about, kind of, how do we make this accessible to everybody, we see it very much as not a ‘one size fits all’, and so we’ve been trying lots of different things to really tackle that, and evolving the approaches which, as you said, that’s where the flexibility comes in.   
 
My hope for the next 12 months is that we can really, now that we’ve got the study up and running, work a lot with the some of the regional networks, the Genomic Medicine Service alliances who are working at the regional level, and the recruiting trusts, to really explore different approaches and work out how we can support them to engage with the communities in their areas, because they’re the ones who will understand who they are, and our role is to really try and provide, as Kerry highlighted, the tools of support to allow them to do that, and to try and make sure that we can make this as equitable as possible in terms of people being able to at least understand the studies here, get the information in the appropriate way, and then as we have also talked about, making their own minds up about whether this is the right thing for them to be part of.   

Vivienne: So, the final question for you all is if I’m a mother-to-be, where can I find out more information. Let’s start with you, Kerry. 

Kerry: Well, from the Generation Study website, there’s information there. Midwives, GP practices, obviously they’re often going to be your first port of call, so I’m hoping that they feel equipped to be able to answer those questions and to signpost people to one of the trusts that are involved.   

Vivienne: And we’ve also got a Genomics 101 episode where we answer some of the frequently asked questions, and I think there are at least 2 or if not 3 separate episodes from Behind the Genes, which people can look for which look at different aspects of the project. Anything else, Alice, that we need to know? 

Alice: So, Kerry highlighted it, the Generation Study website is a really good starting point, but that’s a good place to also find out what trusts are involved because it’s also important to know that this is not available in all trusts in England at the moment. We have a network and it’s growing, and it is all around England, but the first place to start is, kind of, is it in your local trust?  And then from there, it’s then engaging with your trust and hospitals where there will be information, and the midwives are prepared to kind of talk to people.  So those are, kind of, the good first places to start.   

Vivienne: Well, we’re going to wrap up there. It’s been so good talking to you all. So, thank you to our guests Alice Tuff-Lacey, Kerry Leeson-Bevers, and Dalia Kasperaviciute for joining me as we talked through how the Generation Study is continuing to evolve as it responds to emerging challenges.

Now, if you would like to hear more about this, then please subscribe to Behind the Genes on your favourite podcast app and, of course, we hope that you would like to rate this.  Because, if you rate it, it allows more people to see it and more people to get enthused about Behind the Genes, which we love. It’s available through your normal podcast apps. I’ve been your host, Vivienne Parry. The podcast was edited by Bill Griffin at Ventoux Digital, and produced by Naimah Callachand at Genomics England.

Thank you so much for listening. Bye for now.

 

Dr Ana Lisa Tavares, Anne Lennox, Dr Meriel McEntagart, Dr Carlo Rinaldi: Can patient collaboration shape the future of therapies for rare conditions?

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.   

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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 this was going to happen. And I have to say that that was a really reassuring moment in time for us to realise that we weren’t just chasing pipe dreams and trying to do something impossible, that there was a role for us.   

Ana Lisa: I think it would be really interesting for people to hear your story and the amazing set-up and fundraising that you’ve done, and at the same time it would be really good for us to reflect on how this isn’t feasible for every patient and every family and how we’re going to need to work cooperatively to move forwards with rare therapies. 

Anne: When we explored the idea with Professor Muntoni and Meriel and others about setting up a charity one of the really reassuring things that Professor Muntoni got across to us was that this wasn’t about raising the millions and millions it would take to fund clinical trials but the issue in the rare disease space was funding the proof of principle work, the work where you take a scientist’s hypothesis and take it over the line, and the rarer the disease, the less places there are for a scientist to take those ideas. And the example he gave us was a piece of research like that might cost a hundred to a couple of hundred thousand, if you fund a piece of work like that and if it is successful, if the scientist’s principle gets proven, then behind you it’s much easier for the bigger muscle disease charities to also invest in it. It’s harder for them to spread their money across all the very rare diseases hypothesis out there, but if you’ve helped a scientist get over the line they’ll come in behind you and then they won’t be the ones who fund the tens of millions that it takes to run a clinical trial.   

If it’s got potential, then that’s where the commercial world comes in, and that’s where the biotechs come in. So he’d given the example of if you spent £ten0,000 on a piece of research and it actually is proven, in behind you will come the bigger charities that would put in the million that takes it to the next phase, and in behind them will come the bio-checks that’ll provide biotechs that’ll provide the tens of millions.   

And then, you know, a lot of what happens relies on serendipity as well, we know that, and you could easily run away with the idea that you made everything happen but you don’t, you stand on the shoulders of others. And our very first grant application in our first grant round, which received extraordinary peer review for how excellent the application was, was a £100,000 project for a 3-year project that had gene therapy at the core of it by a researcher called Dr Ana Buj Bello at Généthon in Paris. This piece of research was so promising that 18 months in she and another researcher were able to raise $780,000 and, as Professor Muntoni predicted, from the French muscle disease charity AFM and the American muscle diseases charity MDA.  And 18 months into that 3 years it was so promising that a biotech company was started up with $30 million funding, literally just on her work.   

So that doesn’t always happen but, as Professor Muntoni explained, our job was not that $30 million, our job was that first £100,000, and our job was also to make ourselves known to the people in the neuromuscular field.  If you have lab time, if you have research time and you have a choice where you’re putting it there is a place you can go to for a myotubular myopathy related grant application, so it’s not just that this will come to us out of the blue, people will have done prior work, and our existence makes it worth their while, hopefully, to have done that prior work. 

Ana Lisa: That’s an amazing story how you’ve set up this charity and how successful that first application for gene therapy was. I’d love to hear more about that gene therapy and did it get to the clinic and to hear that story from you.  Because I think there are a lot of learnings and it’s really important that the first patients who are treated, the first families that are involved, the researchers who start researching in this area, the first treatments lead the way and we learn for all the other treatments for all the other rare conditions that we hope and that together as a community we can share these learnings. 

Anne: Yeah. I sometimes describe it a bit like going out into space. When you see a rocket going off look at how many people are behind and the amount of work that’s been done, the degree of detail that’s managed, and then you go out into space and there are a whole load of unknowns, and you can’t account for all of them.  Who knows what’s out there in this sphere.  But the amount of preparation, it feels similar to me now, looking back.  We were so idealistic at the beginning.  Our grant to Dr Buj Bello was 2008 and actually it is a really fast time in, the first child was dosed in the gene therapy trial in September 2017. 

Ana Lisa: So, we’re talking less than 1 years. 

Anne: Yeah. And in the meantime obviously as a charity we’re also funding other proof of principle research. One of the founding principles of the charity was to have a really excellent peer review process and scientific advisory board so that we wouldn’t get carried away with excitement about one lab, one research team, that everything would always come back to peer review and would be looked at coldly, objectively. I don’t know how many times I’ve sat in a scientific advisory board meeting with my fingers crossed hoping that a certain application would get through because it looked wonderful to me, and then the peer review comes back and there are things you just don’t know as a patient organisation. So, yes, in those 9 years we were also funding other work. 

Ana Lisa: You’ve just given an interesting perspective on sharing the learnings between the scientists, clinicians, the experts in a particular condition, if you like, and the families, and I’d be really interested to hear your views on what’s been learnt about how families and the patient community can also teach the clinical and scientific community. 

Anne: So, the first child was dosed in September 2017 and by the World Muscle Society Conference 2 years later in October 2019 the biotech had some fantastic results to show. Children who had been 24-hour ventilated were now ventilator-free, which, unless you know what it’s like to have somebody in front of you who’s ventilator-dependent, the idea that they could become ventilator-free is just extraordinary.   

However, one of the things we’ve learnt about gene therapy is that we are going out into space so there are extraordinary things to be found, and extraordinary results are possible, as is evidenced here, but there is so much that we don’t know once we are dealing with gene therapy. So unfortunately, in May, June and August of 2020, 3 little boys died on the clinical trial. So we have a clinical trial where the most extraordinary results are possible, and the worst results are possible, and both of those things are down to the gene…  What we discovered and what is still being uncovered and discovered is that myotubular myopathy is not just a neuromuscular disorder, it is a disorder of the liver too, and these children didn’t die of an immune response, which is what everybody assumes is going to happen in these trials, they died of liver complications.   

And one of the things that has come out of that, well, 2 sides to that. Number one is that it is extraordinary that we have found a treatment that makes every single muscle cell in the body pick up the protein that was missing and produce that protein, but also 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, yes.”   

We could see something that looked like it was not that relevant because it was outside the big picture of the disease, which was about breathing and walking and muscles, but actually there was this thing going on at the same time where the children had liver complications. 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. 

Ana Lisa: Yeah, thank you very much for sharing such a moving story and with such powerful lessons for the whole community about how we listen to the expertise that families have about their condition, and also I think the really important point about how we tackle the research funding so that we’re including and sharing learnings from the conditions that are initially studied in greater depth, and we hope that many more conditions will be better understood and more treatments found and that actually the learnings from these first gene therapy trials will really help inform future trials, not just for gene therapies but also for many other novel therapies that are being developed. 

[Music plays]

If you're enjoying what you've heard today, and you'd like to hear some more great tales from the genomics coalface, why don't you join us on The Road to Genome podcast. Where our host Helen Bethel, chats to the professionals, experts and patients involved in genomics today. In our new series, Helen talks to a fantastic array of guests, including the rapping consultant, clinical geneticist, Professor Julian Barwell, about Fragile X syndrome, cancer genomics and a holistic approach to his practice - a genuine mic-drop of an interview. The Road to Genome is available wherever you get your podcasts.

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Ana Lisa: Carlo, I would really like to come to you about some of the initiatives that are happening in the UK, and particularly it would be really interesting to hear about the UK Platform for Nucleic Acid Therapies as a sort of shining example of trying to do something at a national scale across potentially many different rare conditions.   

Carlo: Thanks, Ana-Lisa. Thanks very much, Anne, for sharing your fantastic story. I mean, I just want to iterate that as clinician scientists we do constantly learn from experiences and constantly learn from you, from the patient community, and this is absolutely valuable to push the boundary. And I really liked your vision of a rocket being launched in space and I would imagine that this is a similar situation here. So, we are facing a major challenge. So, there is over 7,000 rare diseases in the world and with improvements of genetic diagnosis this is only increasing. So, in a way rare diseases is the ultimate frontier of personalised medicine and this poses incredible challenges.  

So, you mentioned the bottom-up approach and the top-down approach and in a way, both are absolutely necessary. So your story is a fantastic story but also makes me think of all the other families where they don’t share perhaps the same spirit, you know, they are in areas of the world that are not as well connected or informed, where patient community simply cannot be ‘nucleated’, let’s say, around the family. So, there is definitely an issue of inclusivity and fair access.   

So, what we’re trying to do at UPNAT, which is the UK Platform for Nucleic Acid Therapy, is to try to streamline the development both at preclinical and clinical level of nucleic acid therapies. So, we’ll start with antisense oligonucleotides just because those are the molecules of the class of drugs that are most ‘mature’, let’s say, in clinic. So, there are several antisense oligonucleotides already approved in the clinic, we know that they are reasonably safe, we understand them quite well, but of course the aspiration is to then progress into other forms of gene therapy, including gene editing approaches, for example.  

And one of the activities that I’m involved, together with Professor Muntoni, is to try to streamline the regulatory process of such therapies and in particular curate a registry of, for example, side effects associated with nucleic acid therapy in the real world, and you would be surprised that this is something that is not yet available.  And the point is exactly that, it’s trying to understand and learn from previous mistakes perhaps or previous experiences more in general.   

And this is very much in synergy with other activities in the UK in the rare disease domain.  I’m thinking of the Rare Disease Therapy Launchpad, I’m thinking of the Oxford Harrington Centre, I am thinking of the recently funded MRC CoRE in Therapeutic Genomics. These are all very synergistic. Our point is we want to try to amplify the voice of the patient, the voice of the clinicians working on rare disease, and we want to systematise. Because of course one of the risks of rare disease therapies is the fragmentation that we do all these things in isolation. And I would argue that the UK at the moment leveraging on the relatively flexible and independent regulatory agencies, such as the MHRA, on the enormous amount of genetics data available through Genomics England, and of course the centralised healthcare system, such as the NHS, is really probably the best place in the world to do research in the rare disease area, and probably I’m allowed to say it because I’m a non-UK native.      

Ana Lisa: Thank you, that’s a brilliant perspective, Carlo, and across all the different therapeutic initiatives that you’re involved with. And, Carlo, presumably - we’re all hoping - these different initiatives will actually lead to ultimately a bigger scaling as more and more novel therapies that target both our RNA and DNA and actually are working, I guess further upstream in the pathway.   

So classically in the past it’s been necessary to work out all the underlying biology, find a druggable target somewhere in that pathway and then get a larger enough clinical trial, which can be nearly impossible with many of the rare and ultra-rare conditions or even, as you’ve said, the sub-setting down of more common condition into rarer subtypes that perhaps can be treated in different ways.  And with the many new different treatments on the horizon, ASO therapies, as you’ve said, is a place that’s rapidly expanding, and also crisper gene editing. I’d be really interested to hear your reflections on how this might scale and also how it might extend to other new treatments. 

Carlo: Yeah, that’s exactly the right word, ‘scaling up’. I mean, there will be of course very unique challenges to every single rare disease but I would argue that with genetic therapies, such as ASOs or crisper gene editing, the amount of functional work that you need to do in a lab to prove yourself and the scientific community that this is the right approach to go for can be certainly very important but can be less just because you’re addressing very directly because of the disease.   

And then there are commonalities to all these approaches and possibly, you know, a platform approach type of regulatory approval might serve in that regard. You know, if you are using the same chemistry of these antisense oligonucleotides and, you know, similar doses, in a way the amount of work that you need to produce to again make sure that the approach is indeed a safe approach and an effective approach might be also reduced.   

I would say that there are also challenges on other aspects of course, as you were saying, Ana-Lisa. Certainly the typical or standard randomised placebo control trial that is the standard and ultimate trial that we use in a clinical setting to prove that a molecule is better than a placebo is many times in the context of rare diseases simply not possible, so we need to think of other ways to prove that a drug is safe and is effective.  

This is something that we all collectively as a scientific community are trying to address, and the alliance with the regulatory agencies, such as the MHRA, and you said that you have found your interaction with the MHRA very positive, and I can tell you exactly the same. So we are all trying to go for the same goal, effectively, so trying to find a way to systematise, platformise these sort of approaches. And I guess starting with antisense oligonucleotides is really the right place to go because it’s a class of drugs that we have known for a long time, and we know it can work. 

Ana Lisa: Meriel, can you tell us a little about the National Genomic Research Library at Genomics England and how this could link with initiatives to find many more patients as new treatments become available for rare and ultra-rare conditions? 

Meriel: Yes, I think what’s wonderful now is actually that what we’re really trying to do is give everybody the opportunity to have their rare condition specifically diagnosed at the molecular level, and the way in which that is being done is by offering whole genome sequencing in the NHS currently in England but to all patients with rare diseases.   

And so, it’s about trying to establish their diagnosis. And as well as that, even if the diagnosis isn’t definitely made at the first pass when the clinical scientists look at the data, because the whole genome has been sequenced, actually all that information about their genome, if they consent, can then be put into the National Genomics Research Library.  And that is a fantastic resource for national and international researchers who get approved to work in this trusted research environment to make new disease gene discoveries and identify these diagnoses for patients. 

What’s also offered by Genomics England as well is when the National Genomics Library data results in a new publication, the discovery of a new gene or perhaps a new molecular mechanism that causes a disease we already know about, that feeds back into the diagnostic discovery pathway within Genomics England back onto the diagnostic side of all the data.   

So, patients who may have had genetic testing previously using whole genome sequencing where they’ve, if you like, had their sequencing done before the diagnosis was sort of known about, will also be picked up. And so, what this is really doing is trying to kind of give this really equal platform for everybody having testing to all have the same opportunity to have their diagnosis made, either on the diagnostic side or with research. 

Ana Lisa: So, sort of on a cohort-wide scale as new discoveries are made and published you can go back and find those patients that may actually have that diagnosis and get it back to them, which is brilliant. 

Meriel: Exactly. And this speeds up the whole process of getting these diagnoses back to people. So on a regular basis in the NHS, we will get feedback from the Diagnostic Discovery Pathway about “Here’s some patients who you requested whole genome sequencing from a number of years ago and actually now we think we know what the particular molecular condition is.”  And so, it’s key of course for our patients with rare conditions to make that molecular diagnosis because then we’re able to have them identified for our colleagues who are doing this ground-breaking research trying to bring therapies for these rare conditions. 

Ana Lisa: Thank you. And I hope that, as currently, if a novel genetic mechanism, as you’ve just described, is identified that could explain a rare condition that those patients can be found and they can receive that diagnosis, even many years later, and hopefully as novel treatments become available and say there’s a chance to individualise ASO therapies, for example, to start with, that one could also go and look for patients with particular variants that could be amenable potentially to that treatment. And that’s really sort of exciting that one could look for those patients across England, irrespective of which clinic they’re under, which specialist they’re under, and I think that could be really powerful as new treatments develop. I suppose, Meriel, if somebody comes to see you now in clinic are things different? 

Meriel: Well, I think one of the things for me when patients come to clinic now is we might have an idea about what we think their condition is, maybe even we think it’s a specific gene. And we can offer whole genome sequencing and so it’s not just the way we used to do things before by looking just at the coding regions of the gene, we can find more unusual ways in which the gene can be perturbed using whole genome sequencing.  But let’s say we don’t make the diagnosis. I encourage my patients, if they’re comfortable with it, to join the National Genomics Research Library, because really it’s been incredibly productive seeing the new genetic discoveries that are coming out of that, but as well I say to them, even if we don’t get the diagnosis the first time round when we look at the data, actually this is a constant cycle of relooking at their data, either if they’re in the NGRL or as well on the Diagnostic Discovery Pathway side of the service that’s run by Genomics England. So yeah, I feel like it’s a very big difference; they don’t have to keep coming every year and saying, “Is there a new test?” because actually they’ve had an excellent test, it’s just developing our skills to really analyse it well. 

Ana Lisa: Yes, and our knowledge, the technology and the skills keep evolving, certainly.  And I think one of the things that I’m sort of hearing from this conversation is that balance of hope and realism, Carlo we were talking about earlier how you need all the pieces of the puzzle to be lined up - so the regulatory agency, the clinicians, all the preclinical work has to have been done, monitoring afterwards for side effects - every piece of the puzzle has to be lined up for a new treatment to make it to a patient.   

And, Anne, I’d like to come back to you because we’ve talked about this before, how one balances these messages of optimism and hope which are needed for bringing everybody together as a community to crack some of these very difficult challenges highlighted by treatments for rare and ultra-rare conditions and at the same time the need for realism, a balance conversation. 

Anne: Yeah, that was one of our big learnings through the gene therapy trial and other trials we’ve had in the condition. As a rare disease charity, you do everything. You know, my title is CEO, but I tell people that’s Chief Everything Officer because there’s only a few of you and you do everything. So, you go and you lead the London Hope Walk and you also are a layperson on the Scientific Advisory Board and you also send out the emails about grants... And so, you could easily as a small rare disease charity conflate different communication messages because you’re in a certain mode.  And so we have been from the early days in the mode of raising hope for people to say, “Look, we can make a difference as a patient community, we could raise funds, we might be able to move things forward, you’ve got the power to make a difference if you want to.” That’s one set of hope.  And it’s not dreamlike hope, we’re linked to the reality of there are great breakthroughs.  So, you know, in the world of spinal muscular atrophy these clinical trials have led somewhere very quickly, so we’re not selling false hope, we’re talking about the difference we can make.   

But then as soon as you flip into “There’s a clinical trial being run” that’s a completely different type of communication and you cannot conflate that message with the previous message.  And we always say to everybody, “We’re your team, we’re a family, we’re a team, we all help each other.  When you are considering joining a clinical trial your team is the clinical trial team.   

The other team does other things for you but the people you need to work with and ask hard questions of and listen hard to, that’s your clinical trial team led by the principal investigator because then you’re in that with them. And, you know, the reality of the fact that many, many clinical trials don’t work as we wish they would be and the decision you make for your child, your baby, your little one, to join a clinical trial… because that’s what it comes down to in our disease, has to be made with that team, not the team that’s selling you a fundraising event. It’s worth reminding rare disease patient organisations we’re wearing different hats and the hope and the realism are different tracks you have to go down.   

But at the same time as being realistic you also have to keep remembering that there is still grounds for hope, we are moving forward. And 21 years ago, when Tom was born the idea that you would be able to get all of the muscles in the body to switch back on – putting it in lay terms – seemed like a bit dream. Well, that is what has happened in the gene therapy clinical trial, we just have to now make it safer and understand more about what we’re dealing with. So, the 2 things, the hope and the realism, do exist side by side. 

Ana Lisa: I think that perfectly encapsulates a lot of the messages around rare disease therapies where there’s such hope that novel treatments will really target directly the DNA or RNA to potentially correct the problem across many different rare conditions and therefore actually making treatments one day suddenly available to a much, much bigger population of people with rare conditions than we could’ve dreamt of 20 years ago or perhaps now, and at the same time this massive need to work cooperatively to all make this as fair, as equitable. Not everybody is going to have the opportunity to fundraise massively to be an expert about their condition, and the importance of sharing these learnings and also really, really listening to the patient community and really, as Carlo was saying, keeping track of side effects, having registries/databases to share these is going to be incredibly important. 

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Ana Lisa:  Anne, can you tell us a little about your reflections on equity from the patient community perspective? 

Anne: Well I mentioned serendipity early and one of the aspects of serendipity that played into our favour for setting up the Myotubular Trust was that by hook or by crook Wendy Hughes, who set up the charity with me, and I were both able to devote time at that period of our lives to setting up a charity. When my husband, Andrew, and I were told that Tom would more than likely die before his first birthday, one of the decisions we made as a family was that he would never not be with a parent, we would always have someone around, and that kind of meant someone had to give up a full-time job and that was me.  We thought, “If Tom has a few scarce months on the planet, we’ll be with him.” And then when Tom lived to be nearly 4, as a family we got used to living on one salary and we were very lucky that we could pay the mortgage that way and run our family that way and eventually that meant I had the time to run the charity.   

That doesn’t happen that easily, that’s a tall order, particularly when you have somebody in the family who has such high needs. And one of the things that I have often thought about is that in the rare disease space we could do with a different funding model for rare disease charities, we could, in an ideal world I have this nirvana that I imagine where there’s a fund that you can apply to that is contributed to by the people who make profits out of finding rare disease cures - so the pharmaceutical companies and the biotechs - and there’s a fund that they contribute to and that if you have a rare disease and you are willing to set up an organisation that supports families, that raises research funds, that provides a way of hearing the patient voice, then you could apply to that for running cost funds and then you’d be able to run this charity. And then you wouldn’t have to rely on whether you live in an area where people will raise money for you or…  We were very lucky that we came across a few great benefactors who would give us money for running the charity, which is actually how we fund it.   

All the research money we raise goes 100% into research, not a penny of it goes towards running costs because we have serendipitously found people who will be benefactors for the charity, but we’re relying on a lot of good luck for that kind of model to work. And when you look at how much profit is made from developing rare disease treatments and cures – which is fine because that’s what puts the passion and that gets people working on it – then why not have an advance fund to run rare disease charities? One of my nirvana dreams. 

Ana Lisa: It’s good to dream. Indeed, my hope is that there will be some amazing shining examples that lead the way that open doors, make things possible, prove that something can work and how and that then that will enable many other treatments for many additional rare conditions to be added in so that if you’ve learnt how this particular treatment modality works for this rare condition and there was funding behind it and everything else that’s needed that then you can, the learning from that, I’m going to use the word ‘tweak’, which sounds minor and could be very major but actually the concept that you can then tweak all those learnings and findings so that that same type of treatment modality could be adapted to treat somebody else with a different rare condition in a different location would be absolutely incredible and really powerful, given that if something like 85% of rare conditions affect less than one in a million people it’s not going to be feasible to use the same strategies that have been used in the past for very common conditions.   

One of the other big barriers is the cost of developing treatment for ultra-rare conditions.  Where it’s a small number of patients that you have and therefore all the challenges that come with monitoring, checking for efficacy, monitoring safety and ultimately funding the challenges are much greater, however if some of these treatment modalities are also going to be used to treat common conditions it might be that actually there’s a lot more cross-talk between the nano-rare, ultra-rare, rare and common conditions and that we can share a lot of that learning. I’d love to hear from each of you where you hope we will be for rare disease and rare therapies. 

Carlo: Well my dream is that 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, the centre, genetics lab, flags that there are the specific mutations, we know exactly which is the best genetic therapy to go after, antisense oligonucleotides as opposed to CRISPR editing, and a path forward, both at the preclinical and clinical level, to demonstrate and to cure these patients eventually is already laid out in front of the patient.  So, transforming the day of their diagnosis as a day of hope, this is my dream with the next ten years. 

Ana Lisa: Thank you, that’s a wonderful dream. Meriel, can I come to you? 

Meriel: Yes, I think I just want to echo Carlo.  We’ve had great developments and progress with getting whole genome sequencing into the NHS for testing but what we really need is for it to be fast and efficient and getting those diagnoses established quickly. And we have had that set up now and we’re really getting there in terms of speed, but then what we need is exactly what’s the next step and actually structure like UPNAT that are developing these processes that we can then say to the patient, “And from there, now that we’ve established your diagnosis, this is what we have options to offer.” 

Ana Lisa: Brilliant. And presumably that if the diagnosis isn’t achieved now there is a hope that it will be achieved in the future as well. Anne... 

Anne: Well, stepping one hundred per cent into the patient’s shoes rather than the scientific side that we don’t so much influence....  stepping in the patient’s shoes, in 5 years’ time I would absolutely love it if we were in a situation where all the parties that have come to the table looking at a therapy or in the earlier research genuinely want to bring the patient voice into the room. As Carlo talked about, there’s even going to be more and more and more of these rare diseases, then those voices, those few people who have experience of it, they may be able to shed light on something. Maybe even sometimes don’t even know it’s a fact that they know but that were brought to the table as passionately as everything else is brought to the table. 

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Ana Lisa: We’ll wrap up there. Thank you so much to our guests, Anne Lennox, Carlo Rinaldi and Meriel McEntagart, for joining me today as we discuss the collaborative power of working together and look to the future of rare therapies that could have the potential to unlock treatments for many rare conditions. If you’d like to hear more like this, please subscribe to Behind the Genes on your favourite podcast app.  Thank you for listening.  I’ve been your host, Ana-Lisa Tavares. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.  

Dr Gavin Arno, Kate Arkell, Bhavini Makwana and Naimah Callachand: Can genomic research close the diagnostic gap in inherited sight loss?

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 who know their genetic diagnosis, they are more able to recognise research that is most relevant to them and quickly pick out potential opportunities to take part. At the moment it is still the case that around 30% of our community who have a genetic test will not receive a clear result, and that can feel very frustrating. So, the more discoveries like this that are made, the better.  

Naimah: Thanks Kate.  So, now we are going to hear a clip from Martin Hills, our Retina UK patient representative who has been diagnosed with autosomal dominant retinitis pigmentosa. Martin has undergone genetic testing and shares more about his experience. 

Martin: My name is Martin Hills, and I was officially diagnosed with autosomal dominant retinitis pigmentosa in 2001, and because of that I immediately had to stop driving which made a huge impact both on myself and my family.  My eyesight has slowly deteriorated over the years. It first started with difficulty seeing at night, and also playing some types of sport, which I think probably was in my 20s. My peripheral vision has been lost slowly and now has completely gone. Fortunately, I still have some reasonable central vision left which is a great help. I am registered as severely sight impaired, and I am also a symbol cane user. My father and aunt were both diagnosed with this condition, and my daughter has been relatively recently, as has altogether eight members of our wider family, and that also includes two younger generations. In 2015 I went for genetic counselling and testing and at that time it was for 176 genes known to be associated with retinal dystrophies. I believe that has now gone up to about 300, but at the time they couldn’t recognise what my faulty gene was, and that has still been the case to my knowledge to date.  

I have also been part of the 100,000 Genome Project along with several others of my wider family, and I am also a participant in the UK Inherited Retinal Dystrophy Consortium RP Genome Project, which has been sponsored by Retina UK. The impact of not having a positive genetic test result is quite interesting and has really been a rollercoaster. I guess it is all about hope, and to start with when I knew I was going to be genetically tested, I think my first reaction was optimism, and I think if you have a positive test result, that is a real hope for the future. I think that is quite exciting particularly as things seem to be progressing so rapidly. But because I didn’t get a positive result, the next reaction I had really was disappointment because I felt one step behind people with a positive result. Of course the natural reactions are one of frustration, and then I guess followed by realisation of the situation, and heading towards trying to adjust and making coping strategies for the future.  I still feel that genetic testing for all forms of medical conditions is so important and has a huge future in understanding and then potential treatments for so many medical issues. I guess it might be a bit too late for me, but if I can contribute to finding a restorative treatment for the younger generations of my family, and for that matter other people, then I think that is good enough for me.  

Naimah: So, we have just heard from Martin that although he has not been able to have a positive genetic test result, his involvement in various studies may have benefits in helping others find treatment. So, I guess on that point Bhavini, maybe you could comment, or ask you how you felt whenever you were about to get a diagnosis through whole genome sequencing? 

Bhavini: Yes. When I got called in almost three and a half years after the testing that took place was a massive, massive relief because not only did I get genetic counselling before the testing period, but I got called in and I spoke to a genetic counsellor who explained what they had been able to find and what kind of RP it was, how it would progress, and just answer so many questions. I am the mother of two daughters and even having two children, I lost a lot of sight after my first daughter, but at that time there wasn’t any evidence or there wasn’t any … you know, there was nothing I even knew about what questions to ask or anything, so I did go on to have a second child and drastically lost more sight. I had always been told, because the lack of awareness and understanding of RP in my family, and I am one of four children, and I am the only one that has it, so there is no other family history. Now I know it could have skipped generations, but I was always told things like it was karma. I must have done something in my past life. I was told to kind of have these herbs or these remedies to cure my sight loss, you know my RP. I was even desperate enough to kind of …  all these bogues treatments that you find online. You know, anything. I was so desperate to find anything that would help me.  

When I received that testing and the counselling, it explained so much about how my daughters may or may not be affected, how they are carriers, and that was explained to me, how it would progress. So many questions and worries that I had for almost a decade and a half, they were answered. And not only for me, for my family, and all those people that told me all these sorts of things that I used to worry about that could have caused my RP. I was able to explain it to them and they understood that it was nothing to do with me being bad in my past life. It was actually you know, there is something scientific about it. So, it kind of gave me lots and lots of answers, and actually I then created a private Facebook page just with my RP26 CERKL genetic that I have been diagnosed with, just to see if there is anybody else out there, because when I was diagnosed, I think at the time I was told there was only myself and nine other families in the UK diagnosed with this particular gene. Now, I haven’t been that active on it, but you know there are people across the world who found my post and joined the group, and we share experiences about the age that we were kind of diagnosed, the kind of rate the symptoms have developed. It is so fascinating because we have got such similar experiences.  

There is parents on there who are there on behalf of their children, and it is just so nice to see … I know it is RP, but the specific gene and the rate of which we have experienced all the symptoms, it is quite similar. So, it has been quite supportive and helpful and reassuring to my family including my daughters. 

Naimah: That’s incredible Bhavini and it’s really nice that you have created that group and created kind of like a support network for all the other families that have been affected by the same genetic condition as well. Yeah, that’s incredible. Gavin, I know the findings in the study show that the genetic changes in this study are more common in people of African and South Asian ancestry. So, so I want to understand why is this an impactful finding in the study? 

Gavin: Yes, so Kate mentioned that around 30% of people with inherited retinal dystrophies who have genetic testing don’t get a molecular diagnosis and we are working in my research lab and many other research labs to improve that. Now, that figure is very much higher in patients of for example African ancestry in the UK, and this is partly due to the fact that historically and even now genetic studies have been focused on European individuals and taken place in the US, and the UK, and Europe, and wealthy countries across the world. This means that people of African ancestry are poorly represented in genetic studies, not just genetic studies of genetic disease, but population studies as well. So, we have less of an understanding of the genetic variants found in the genomes of individuals of African ancestry. So, that means we solve less of the genetic cases, particularly at Moorfields we published a paper on this several years ago with the diagnostic rates in European patients versus those of African ancestry, and it was very, very much lower. So, we need to do better for those patients, and this study identified a cause of retinitis pigmentosa in 18 families of African ancestry who were recruited to the 100,000 Genomes Project.  

This is a fairly large proportion of the patients with RP of African ancestry seen at Moorfields Eye Hospital, and when we contacted collaborators around the world many more families were identified, and I think we ended up publishing around about 40 families who were affected by this particular mutation. So, we can look at that variant, we can look at the DNA sequence around that variant, and we found there is a chunk of DNA around the mutation in the gene that was coinherited by all of those different individuals. So, this is what we call an ancestral haplotype. It’s an ancient variant that goes back many, many generations and it has a fairly high carrier frequency in genomes of African ancestry. So, we think this will be a fairly significant cause of retinitis pigmentosa across the continent of Africa. And so, identifying it will enable us to provide a molecular diagnosis for those families. Potentially there will be many more families out there who don’t know they have this cause of disease yet. They may be affected but they haven’t yet received genetic testing.  

But 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. As Kate mentioned many of the gene therapies are gene specific, so if we identify a cause of disease that is predominant like this and affects many, many people, then of course there is more interest from the pharmaceutical industry to develop a therapy for that specific gene. 

Naimah: Thanks Gavin. I think that really does showcase how impactful these findings really are. Kate, can I come to you. So, Gavin touched on it there that people with African and Asian ancestry are significantly less likely to get diagnosed, but why is it important to ensure that these groups are represented in the genomic datasets? 

Kate: So, we need to ensure that genetic testing and diagnostic accuracy works for everyone, and not just those of European ancestry. So, as Gavin said if the datasets don’t reflect the genetic variations seen in African or Asian populations, then the tests based on those data are more likely to give incomplete results for those groups of people. We really need a diverse range of genetic information for researchers to work on. As it is clear from this study’s results, populations from African backgrounds for example may have unique genetic mutations linked to retinal dystrophy. So, if those are really underrepresented in datasets based on European populations, that is obviously going to present a problem. Gavin mentioned access to treatment. We need to overcome some of these disparities in healthcare access, and   inclusion of broad spectrum of genetic data is actually a foundation for that.  

Naimah: Thanks Kate. 

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If you're enjoying what you've heard today, and you'd like to hear some more great tales from the genomics coalface, why don't you join us on The Road to Genome podcast. Where our host Helen Bethel, chats to the professionals, experts and patients involved in genomics today. In our new series, Helen talks to a fantastic array of guests, including the rapping consultant, clinical geneticist, Professor Julian Barwell, about Fragile X syndrome, cancer genomics and a holistic approach to his practice - a genuine mic-drop of an interview. The Road to Genome is available wherever you get your podcasts.

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Naimah: So underrepresented groups are often less likely to know about genetic testing due to a combination of social economic and systemic factors that create barriers to access information. Cultural taboos can also play a significant role in shaping attitudes towards genetic testing, and I think Bhavini you kind of touched on this slightly with some of your experiences. I wonder, did you experience any of these cultural taboos? 

Bhavini: Yes, some of them, but I think by the time I was informed about what genetic testing and counselling is I had come across Retina UK and I had already started having that background knowledge, so when that was offered to me, I actually had a basic understanding. But as Chair of BAME Vision I work with a lot of ethnic communities, and when I speak about my own personal experience about receiving genetic testing and counselling, I kind of break it down into my own language, and the few common themes that always come out is 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.  So, again there is already a taboo around the terminology. Then it is lack of understanding and awareness, or where to get that information from. 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 outcaste in the community and the wider family, and you will be frowned upon, people will talk really bad.  

So, it is not really common knowledge, so they don’t even talk about it. So, there is a lot of layers to unpick there. That is one of the priority areas in 2025 that we at BAME Vision are going to be working on to try and raise that awareness in different communities about what genetic testing is, what it could mean, how to get genetic testing if it is not offered to you at your own clinic. There is a lot of work I know Retina UK have done, so working with them, and how we can reach different communities to raise that awareness. 

Naimah: That’s great. You have touched on how important the education piece is. I wonder, do you have any other examples of how healthcare providers and genetic counsellors might better engage communities to ensure that they are receiving the care that they need? 

Bhavini: Yeah, absolutely. So, I think having information in different languages is essential, and I don’t expect to have lots and lots of leaflets in different languages. Whether it is audio form or whether there is different professionals within that setting that speak different languages that can communicate to those patients, or even their family or friends that could translate. I think language is definitely something. And having representation, so like different people who have accessed this and sharing their story and going out into community groups and sort of sharing those messages, is definitely what has been working for us, and we have been doing that on other topics that we have used. 

Naimah: Yes, they all sound like really important ways to try and engage with different communities. You have already mentioned how amazing that Retina UK have been and the support that you have received from them. So, I wonder Kate, if you could tell us a bit more about the support that is available for those with inherited sight loss, and how these resources can support people from underrepresented groups as well. 

Kate: So, we have a range of support services at Retina UK most of which involve our fantastic team of volunteers, one of whom is Bhavini, who are all personally affected by inherited retinal dystrophy themselves. So, they are all experts by experience so to speak. The team also does include members of the Asian community as well. So, if somebody makes a call to our helpline, they will be able to speak to somebody who genuinely understands what they are going through, which can be a lifeline for those who are feeling isolated and especially I think as Bhavini mentioned, if they feel unable to talk openly with their own family and certainly within their community. We have a talk and support service that offers ongoing more regular telephone support as well as in-person and online peer support groups where people can make social connections with others in similar situations. I think Bhavini has mentioned that she herself runs our London and Southeast local group.  We also have an information resource called Unlock Genetics. That explains genetics in understandable language and clearly explains how people can access testing and what that will involve. So, we have stories on there from people who have gone through the process and talk about that. So, that is available on our website, and we can provide it in audio format as well. 

Naimah: So Gavin, looking to the future, what does this research mean for patients with sight loss and their families? What does this mean in the future? 

Gavin: So, I think now that we have access to whole genome sequencing through projects like the 100,000 Genomes Project, we are able to start the process of understanding new causes of disease that are found outside of the coded region.  So, we can now look for non-coding variants that cause disease which was previously not possible because genetic testing was focused on 2% of the genome. As we make discoveries like this these will inform future studies. So, the more we identify this type of variant and are able to functionally test the effect on the gene or the protein, we are able to use that information to lead future tests. What this needs is large population datasets to be able to analyse these sorts of variants at scale. The more genomes we have the better our understanding will be of our population frequencies, and the key thing is here for inherited retinal dystrophies, all of these variants that we are identifying are very, very rare. So, we only find them in a very small number of individuals affected with disease, and an infinitely smaller number of individuals in the unaffected general population. So, the larger that population dataset is that we can study, the better we can understand the rarity of these variants and pick those out from the many, many millions of non-pathogenic or harmless variants that we find in the genomes of all the individuals. 

Naimah: Do you think the paper will help lead the way for diagnosis of other conditions in African and South Asian communities?   

Gavin: Yes. The better we understand causes like this, and we are now at the point where most of the genes that cause retinal dystrophy have been identified already, so the remaining causes to be identified will be these more difficult to find cases, non-coding variants, structural variants, which we haven’t touched on today which are larger rearrangements of the genome. These things are harder to find, harder to interpret, so the more that we find like this, the better our ability will be to interpret those sorts of variants. There are many similar findings coming out of genome studies like 100,000 Genomes Project. For example, there was a significant finding recently published on a non-coding RNU gene which causes a significant proportion of neurological disorders in the 100,000 Genomes Project. You need these studies to be able to drive forward the research in areas like this.  

Naimah: Thanks Gavin, and the discovery that you are mentioning is the RNU4-2 gene that was discovered earlier this year. You can hear more about that on our other podcast on our website which is ‘How has groundbreaking genome work discovery impacted thousands far and wide’ to learn more about that as well. But yeah, I agree it is another really great example of how impactful these findings can be.

Okay, we’ll wrap up there. Thank you to our guests Gavin Arno, Kate Arkell, and Bhavini Makwana for joining me today as we discussed the findings from a recent study which has identified genetic changes responsible for retinal dystrophy, and people commonly of South Asian and African ancestry. If you’d like to hear more like this, please subscribe to Behind the Genes on your favourite podcast app. Thank you for listening. I have been your host and producer, Naimah Callachand, and this podcast was edited by Bill Griffin of Ventoux Digital.

Dr Natalie Banner, Dr Raghib Ali, Professor Naomi Allen, Dr Andrea Ramírez: How can we unlock the potential of large-scale health datasets?

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 practice.  

Andrea: Absolutely, and that dialogue and understanding and learning from each other both informally in meetings and talking as well through the published literature. So, all of these datasets are actively widely used, and seeing what is coming out in publications helps us know what researchers are doing with the data. And when you see different researchers either generating hypotheses from our datasets in a different way, or testing hypotheses differently, that helps us understand where some benefit might be added to our dataset or where we really may need to grow in a different direction to meet some other research needs.  

I think that every study design always struggles with that balance between knowing exactly what we want to study and therefore building very specific questions and very specific protocols, but also allowing for the knowledge that we don’t really know all of the discovery we need to make and bringing in datapoints that will really generate those new hypotheses for the future.   

 I think for our study in particular, UK Biobank has been so remarkable in this way, helping structure All of Us to be able to contact our participants like UK Biobank and say, “Hey, we didn’t really know what we were going to get, but we have put all this wonderful data together and now we need to do a deeper dive.”  

So, the engagement and long-term return of those UK Biobank participants has really enriched our data, and we have learnt from UK Biobank a lot there, and hope through growing our partnerships programme that we can continue to create partnered research opportunities to strengthen that data as well. That is a new thing coming out of our group. You may have heard of it previously as ancillary studies, but we recognise the partnership that is important for those research opportunities. So, we are reporting here that we are hoping to rebrand it to reach a larger audience, and that is led by Dr. Shelley, as partnered research opportunities that will allow us to re-contact, bring our participants back, and really deepen that dataset.  

Natalie: Thank you. And Raghib, I know that it is a really important part of the Our Future Health model about going back to participants, but you are in quite early stages of working out what those opportunities might look like.  

Raghib: Yes, very much early stages. Just to reiterate the point for me personally, having started my research in the UK about 20 years ago, I have certainly learnt a lot personally, but we have all learnt a lot from the model that UK Biobank established in terms of collecting data and providing it to researchers, and I see these 3 studies as very much complimentary.  

All of Us again have done a lot more work in terms of providing feedback to participants about their risk of disease and genetic information, and as you say Our Future Health was set up deliberately to not just be a purely observational study, but to give participants feedback about their risk of different chronic diseases as well as the opportunity to take part in not just studies to collect data, but also interventional studies to see if we can change the natural history of disease and prevent diseases in our participants.  

So, that has never really been done at scale before, and that is certainly a big challenge for us to do, not just in the UK, but anywhere, including the US and working with health systems as to how best to do that. So, you know we have spent the last 2 years really trying to understand how best to recruit participants and to provide data to researchers for the next couple of years, and long beyond that we will be looking really as to how we can maximise the benefits of providing feedback to participants and taking part in interventional studies.  

Naomi: I think one way in which we can all learn from each other actually, is we know how to recruit hundreds of thousands of people, the general population, into research study, and the next challenge is how do you keep engaging them, telling them what you are doing. You can't collect everything when they first join the study, or they would be with you for days. So, what UK Biobank has been doing is sending out web-based questionnaires, a couple a year, to find out extra information about health outcomes, lifestyle factors. Inviting them back to specific assessment centres.  

So, we are inviting 100,000 participants back for imaging, and then again over the next few years for a second scan. So, I think the real challenge here is once you have recruited them, how to find that right cadence of engaging those participants to keep contributing their data and their biological samples to really maximise the value of the dataset for research. That is an ongoing challenge for all of us. But I have to say, the UK Biobank participants, they are an amazing group of individuals, very altruistic.  

Our Future Health and All of Us, we don’t give feedback, so there is nothing in it for our participants other than knowing that their data may help the future health of their children, and their grandchildren, and the rest of the world. So, that is very humbling, to know that the data that they have generated, and we have collected on them, is being used in that way.  

Natalie: That’s a really interesting point, Naomi, about the difference between a research study that is designed for answering a particular question. You gather specific data for a specific purpose, and when it comes to recruiting participants into that you can be very clear about what it is you are trying to do.  

But of course, for all of these programmes, the whole nature of them is that you are collecting a lot of data over a long period of time, and it could be used for all sorts of different purposes. You can't say at the outset exactly what those purposes might be and what those outcomes might be. So, there is a really interesting question, and of course I would say this with my ethics hat on, a really interesting question around sort of participant trust and confidence in those programmes.  

Naomi, you spoke just then about one way of retaining engagement and retaining people’s interest, but I wonder Raghib and Andrea, if you have got thoughts on those sort of questions of how you can create that environment where participants can trust what you are doing with data over a long period of time, when you can't at the point at which they consent, say exactly how that data might be used? You have got a sense of the kinds of purposes, but you can't be too specific       

 Andrea: Sure. We know, and I have learnt from my own peers in this role, that enrolment in the study isn’t the end point of engagement. All of Us’s approach on engagement has been communicating with the entire community and really being there in the community, and that has been very powerful.  

One effort over the last year we are proud of has been what we are dubbing participant driven enquiry, and that is where we say, “Thank you participants. We have gotten a ton of data out there for use, and funded researchers to use it all the time, but what do you, the participants, really want?” We were able to then take papers that researchers write and help tell participants and explain it in lay language, so the participants can say, “Hey, I have a question. Could you answer that for me?” Maybe we can, maybe we can't, but it has been very interesting to hear what participants want to know, and that participant driven enquiry project has turned out to be a big opportunity there.   

The question they came to was not easy. Certainly, we didn’t expect an easy question, but they came to us asking, “Why is my diabetes worse than someone else’s? Is it the environment? Is it my genome? Is it my access to care? Why can't my diabetes be as well controlled as someone else’s?”  So, that has been huge, to interact directly with our participants and help really close the loop by answering questions in the language of research and show them how their data is contributing back.   

Natalie: Thank you. And Raghib, how are you sort of grappling with these questions, particularly because you are recruiting so very heavily at the moment?  

Raghib: So, as you say it is a challenge, and people do join the programme primarily based on trust that we will use their data for public health benefit and for the benefit of the whole population, but they also join on the basis that they will get back information about their own health and their risk of disease. To do both of those is not straightforward. I mean, the first of those, it has been well established by UK Biobank, and about 80% of our participants also say they are doing it primarily for to altruistic reasons, which is great. But 80% also said they would like to receive feedback about their own health, which is also understandable, and so we need to find ways to provide that in a timely way, but also in a way that the health service can manage. That is going to be one of our key challenges going forward.   

But to echo what Naomi and Andrea have said, I mean to maintain participant’s engagement with the programme is not easy. We need to make sure that they are receiving information regularly, are kept up to date with what we are doing with their data, with the work that we are doing with academia, with the NHS, with industry etc. It is easier now than it was before because Our Future Health has been set up as a digital cohort, so we have means of communicating much more easily with our participants. But yeah, as you say we are at early stages. Over time that does get harder, to maintain that engagement. So, we know in the next one to 2 years we need to step up our work on feedback and recontact.  

Natalie: Fantastic. I really love the idea of like the participant-led enquiry. That is something that I think our participant panel at Genomics England would really like to hear more about.  

So, speaking about sort of ongoing engagement with participants, one of the challenges we know around recruiting into large-scale studies like this is that many research datasets don’t have equal representation from all communities. That might have an impact on the quality, the representativeness of the scientific outputs that you can generate, and potentially the benefits back to patients and participants.  

How are you addressing this challenge in recruitment where you may have some communities that are not as engaged with scientific research. You may have elements of distrust or people being marginalised, having difficulty accessing research and these sorts of opportunities. Do you have any examples of what has worked really well? Raghib, if I could come to you first.  

Raghib: Sure. So, I mentioned I worked on UK Biobank about 20 years ago. One of the things I was looking at then was how we could maximise participation, particularly of people from ethnic minorities into the project. Because of the age group that was chosen by UK Biobank for very good reasons, age 40 to 69, the proportion of people from ethnic minorities was relatively small. So, although it was representative for that age group, I think it was about 6%, or 34,000 out of the 500,000, that were from non-white ethnic minorities.  

So, when Our Future Health was set up, we knew that the population has changed anyway. You know, the UK has become a much more ethnically diverse society. But also, because it is a cohort from 18+ and I think minorities tend to be younger on average than the white population, we knew we had an opportunity to really have a big step change in the number of people that could take part in a study like this. So, our aim is actually to get 10% of the whole cohort from ethnic minorities, so 500,000 out of the 5 million from ethnic minorities. Actually, so far we are pretty much on track. So, of the 1.8 million that have consented, about 180,000 are from non-white ethnic minorities.  

That is extremely important, particularly for genetic research where non-European populations are very much underrepresented in nearly all genetic databases. Secondly, from a UK context, although it applies of course in all countries, is that people from more deprived backgrounds are also less likely to take part in this type of research. So again, we have made a very deliberate attempt to try and ensure we have adequate numbers from the most deprived quintile. Again, about 10% of the cohort so far, nearly 200,000 are from that most deprived quintile who both are underrepresented in research, but also have the worst outcomes. So, this is really our first study that has been big enough in the UK to look at that group properly and understand some of the factors at an individual level that we haven’t been able to in the past.  

Finally, geographically, so the first time again because it is a digital cohort, we were able to recruit people from all over the UK. So, every single part of the UK is now represented in Our Future Health, particularly coastal communities and rural areas that haven’t been able to take part in this type of study before, as well as Northern Ireland. You know, for the first time we have got that full geographical coverage.  

Natalie: Fantastic. I suppose a lot of that recruitment approach has very much been about going to where people are, rather than expecting them to come to you. Is that right?   

 Raghib: That is right and thank you for reminding me. So yeah, we have had a different approach. So, we have opened up many, many more clinics than previous studies through a combination of mobile units, shopping centres, community pharmacy. Community pharmacy in particular has been very important. So, to date we have had about 400 different venues that we have been able to recruit. That is over 1 million people that have given blood samples, and that has really enabled people from every part of the country to take part. Secondly, we have kept clinics open in areas of greater deprivation and ethnic diversity much longer than in other areas, to maximise the opportunity for them to join. Thirdly, we do provide reimbursement for people with expenses to ensure they aren’t excluded because of financial reasons, and again that has helped.   

Natalie: So, really making those efforts is evidently paying off. Andrea, have you had similar experiences as All of Us? What has your approach been to try and ensure that you are getting a wider representation from different communities?  

 Andrea: It has really been a focus on the programme from the start to engage those who have not been included in research in the past and make sure the opportunity is there to participate. Our Engagement Division, led by Dr. Corrine Watson has really pioneered reaching those communities here in the US.  

I think one other thing I will mention that we think about when we think about how to engage participants and reach people to return value back to those communities, is to make sure the people who are accessing the data also represent them, and we can build diversity within that researcher workforce. So, since our data was first released in 2020, we have recognised that the biomedical workforce also has a huge group of underrepresented individuals, and a lot of our researcher engagement and researcher outreach has focused on reaching those of diverse backgrounds and career paths.  

To that end we have reached out and engaged historically black colleges as well as other minority serving institutions, really looking to make sure that their students and researchers can have the same access as more traditional research-based institutions in the US system.   

That has been important because our system is built on cloud-based architecture and shared data that doesn’t require a huge cluster on campus, and that helps remove a barrier that some of those institutions and researchers may have had. We also know they haven’t been able to participate in the past, and we think that cloud architecture again can make the data much more feasible and be a huge support to diversifying the researcher workforce as we go forward. That circling back, helping them be the voices speaking to their community, helps build out that diverse participant community base as well.   

Natalie: That’s such an important point, because it is not just about the participants and the data you can collect, but also who is able to look at it? Who is actually able to undertake the research?   

Naomi, can I bring you in here? I know that UK Biobank has been thinking a lot about researcher access to data and trying to ensure that the data that you hold, the really rich datasets you hold in UK Biobank, are more accessible to researchers from different backgrounds who may not have the same level of resources. Can you tell us a little bit about the work you have been doing on that?  

Naomi: Yeah. So, just following on from what Andrea said, it is really important to get as diverse ideas as possible from across the global research community to really move public health forward.  

So, what UK Biobank has done is we are putting mechanisms in place so that early career students, and career researchers, and researchers at all levels of their career from lower income countries, can access the data at a much lower fee. So, currently for most researchers it costs about £9,000 to access all of the data. So, that is 40 petabytes of genomic data, biomarkers, clinical outcomes, lifestyle factors and so on. So, early career researchers and those in lower income countries, it is about £500.  

On top of that a group of big pharmaceutical companies have got together to create a global researcher access fund, which essentially covers this reduced fee so that all researchers no matter where they are from have exactly the same opportunity to access the data to advanced scientific discoveries. So, on top of that all our researchers now use our online secure research analysis platform. While there is no charge to access the platform, there are costs associated with compute needed to analyse and store the results.   

So, AWS have donated research credits for early career researchers and those from lower income countries up to a total of about $500,000 per year, to use the research platform. So, researchers can apply to use these research credits to offset the costs of compute and storage. So, that means that we are trying to democratise access to researchers from all around the world.  

I think actually our biggest challenge is not so much … we have largely dealt with you know subsidising the cost. It is actually making researchers from lower income countries aware that these resources exist, and that are applicable to them.  

So, sometimes we hear from say researchers in Africa or South America, “Well, there is no point accessing UK Biobank because it is not relevant to our population.” You know, a third of our researchers are from China. So, even if UK Biobank hasn’t got coverage of those racial ethnic populations, that doesn’t mean that the associations that you find between risk factors and disease risk are not applicable to other different populations. And that is also why having different resources like UK Biobank, like Our Future Health, like All of Us, in different populations around the world, is so important in order to replicate those findings.   

Natalie: Absolutely, and fantastic just to hear the attention that is being paid to trying to ensure that diversity of different types of researchers who will just bring different questions to the table, different perspectives on the data, different priorities, different types of questions.   

So, speaking about that diversity of researchers, one really important part of his ecosystem that we haven’t really touched on so far is around the role of industry. There are a lot of really important research questions being addressed by industry. Some that can only really come from, maybe it is pharmaceuticals, maybe it is tech.  

From your perspectives, what kind of role can and should industry and commercial partners play in supporting the kinds of long-term research studies that you have set up, and ultimately trying to get to that point of sort of generating benefits back to patients and health systems. Naomi, can I start with you, for that sort of longer-term perspective for Biobank?  

Naomi: So, industry are great partners for long-term studies like ours because they can bring additional funding, expertise, and technology. So, for UK Biobank, because it is so easily accessible to industry and academics alike on exactly the same terms, what it has meant is that industry, particularly big pharma and also now big tech, they can access the data, they see the value of the data for their own research purposes, and then they have invested into UK Biobank to do whole-exome sequencing, whole genome sequencing, proteomics at scale to increase the value of the dataset for their own drug discovery pipelines.  

But of course, it means that the data that they have generated, which cost millions of dollars to generate, when you need deep pockets to do these kinds of study enhancements, then become available to all researchers. So, having access to these large-scale resources that have deep data on genomics, physical measures, other biomarkers, and clinical outcomes enables pharma to rapidly increase their drug discovery pipelines in generating new drugs and treatments for patients, and also those data are then shared with the rest of the global research community.   

 So, we found it to be a really exciting win/win in which industry get what they need to help move forward new drug targets and discovery, but also other researchers get what they need in order to make other scientific discoveries in different fields of research.       

Natalie: Thank you. And Raghib, I know that for Our Future Health, that industry relationship is a really important part of the founding model. Will you tell us a little bit about how you are engaging and working with industry partners?  

Raghib: Sure. So, as you said Our Future Health was set up in a different way, as a very public private partnership. Although the largest funder is the UK Government, more than half of our funding has come from a combination of life science companies, so pharmaceutical, diagnostic companies, as well as the medical charities, so the larger medical charities in the UK. That partnership is deliberate for all the reasons that Naomi has outlined. 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. So, we have 16 life sciences companies that have joined as founding partners with Our Future Health who have contributed financially to the programme.   

Equally importantly they have also contributed scientifically, so there is a huge amount of scientific expertise in industry, and they work with us with our Scientific Advisory Board with our scientists internally to think about the best use of the resource for drug discovery, diagnostics, new medical technologies, and new targets etc.   

So, that is the vision, and so far, it is working well. It is a relatively new model to have set up a project like this in this way, but it has been a very collaborative approach, and we all recognise, all have similar aims, so recognise what we are working towards. You know, we meet regularly. We have a Joint Founders Board where as I say academia, NHS, industry, and the charities come together to decide on the priorities for the coming years.  

Natalie: Fantastic. And Andrea, I suppose in the US it might be slightly different culturally from the UK, but the role of industry with All of Us, how are you engaging with those pharmaceutical, technology bodies, and partners as well?   

 Andrea: Absolutely, and maybe this goes back a bit to your first question. We at All of Us love learning from UK Biobank and have really seen them forge a lot of wonderful partnerships that have enriched and developed their dataset. We at All of Us have started with academia and working through partnership opportunities really intramurally at intramural centres that make up parts of the National Institute of Health. We believe that building on those close friends and family relationships we have both in the government and academia get us through our first step to be able to interface with commercial organisations. That really started with taking the first step this year to ensure broad availability of data that can maximise both use of the data available, as well as look forward to our partnership opportunities in the future.  

So, commercial organisations as of 2024 have also been able to access the All of Us dataset that is that first step in thinking about what a partnership would be, and we are glad to build on the access that international organisations and academic organisations already have.  

Natalie: A lot to look forward to here. We are going to have to wrap up in a moment, so I’d just like to leave you all with a final question before we have to end the podcast. There is huge ambition in all of the research programmes that you are leading and involved in, but what are you most excited about coming down the line in the next few years? What do you think is going to be feasible? What really gets you excited about the work that you are doing and where you see the potential benefits really landing in the next few years? Andrea, would you like to start?  

Andrea: Thanks. There is a lot we are really excited about. I haven’t had a chance yet to mention our paediatric cohort, and that in addition to expanding access for international research, in 2024 we were able to enrol our first paediatric participants. That really sets up the potential to observe participants across the lifespan. That is a huge advance for All of Us and we are excited about the paediatric work going forward.   

Natalie: I love that, how do you come into the future with us? That is fantastic. Naomi.  

Naomi: Yeah, if I had to choose one would be the possibility of being able to measure circulating proteins on all half a million participants. We have done this on about 55,000 participants, and just that subset alone is already generating fascinating insights for early biomarkers for disease through protein profiles and risk prediction of disease. I think having that on all half a million coupled with their genomics data and health outcomes, will bring a sea change in how we diagnose disease earlier. So, I think that is a really exciting avenue for us to go into over the next couple of years.  

Natalie: Really enriching. That data sounds like a very exciting set of possibilities. Raghib.  

Raghib: Thank you. There are so many opportunities here, but I will just maybe mention 3. So, the first, in terms of being able to combine the genetic data that we are collecting and all the other information about risk factors, and particularly the fact that we have this on a lot of young people, will enable us to identify people at high risk of diseases in the presymptomatic phase and then to be able to offer them both feedback about their risk of disease but also interventions that can change their natural incidences. That has never really been possible before. That is extremely important for all diseases for people, but also it is very important for our healthcare system.  

So, those of you listening in the UK, I know the NHS is under a huge amount of pressure, and the current model of healthcare which has been in place really since the inception of the NHS, is to treat late-stage disease when people have already developed symptoms and signs. You know, it wasn’t really possible to identify people earlier, but it is now, and Our Future Health will provide the evidence base to show that prevention really is better than cure, and to show that these approaches both lead to better clinical outcomes, but also are cost effective and a good use of resources. Of course, the new government is very much committed to this as well, you know moving from acute care to prevention, from hospitals to community, and from analogue to digital.    

Finally, because our cohort has now become so large and does cover every part of the UK, and this wasn’t something I necessarily thought about when we started Our Future Health, we are able to have unique insights into the health of the population across every age group, across every ethnic group, across every geographical area, and by deprivation, and to understand not just observationally in terms of risk factors, but also the impact of interventions on those different populations.  

We can look at that, as I said at an individual level on millions of people to gain intelligence about what is going on in terms of public health, but also to see what will hopefully improve their health in the future. So, there are really, you know I have described transformational opportunities to improve health through both biomedical research and populational health insights now through the resource, and I look forward to working with colleagues across the UK and globally to deliver them.  

Natalie: We will wrap up there. Thank you so much to our guests, Dr Raghib Ali, Professor Naomi Allen, and Dr Andrea Ramírez for joining me today as we discussed how collaboration, scale, ongoing engagement, can really unlock the potential of large-scale health datasets to drive brilliant new research and ultimately improve the lives of patients and the population.  

If you would like to hear more like this, please subscribe to Behind the Genes on your favourite podcast app. Thank you for listening. I have been your host, Natalie Banner. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.

John Pullinger: What is the diagnostic odyssey?

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.

Jillian Hastings Ward, Dr Karen Low and Lindsay Randall: How can parental insights transform care for rare genetic conditions?

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 gap in parents’ understanding because you don’t necessarily know what the next ten years might look like for example. And so, I think making connections with people who are in that age bracket can be really important, but it’s very hard to do.

So Lindsay, I’m conscious that your professional training as a nurse must have stood you in quite good stead when you were faced with a barrage of medical literature shortly after your diagnosis, but I think one thing that every parent shares is the desire to do the best for their child and especially in this world of rare disorders. There’s a huge amount of energy that comes through the community I think, faced with the need to try and self-start and build these networks and connections for themselves. Is that something that you’ve seen in your community as your experience?

Lindsay: Yes, definitely. I think we’re a growing community and over the years of course more and more children and young adults have been diagnosed with a few older adults coming through. It is very much a global networking effort and parent/patient organisations have been set up in many countries now by parents of children with children with SLC6A1. I definitely think that drive to become an expert in your child’s condition is a long journey and one of continual learning and actually a lot of families simply don’t have a capacity to take that on, I think often the medical and scientific jargon is difficult to understand and that makes it challenging to access.

And as you said, as a paediatric nurse, I at least have some existing skills to understand healthcare to read the research and speak with medical and scientific professionals with some confidence, but in some ways, that has increased the burden I’ve placed on myself to become an expert for my children and other children and families who are not in the same position as me.

It does require a lot of dedication and time, and that does have implications on families because it’s time away from our children and from home, and from the remnants of our lives that we desperately try to cling onto, to not lose all sense of ourselves. It’s not often spoken about but I do see the strain it places on the families, as well where there’s a lot of separation and divorce sadly in the rare disease communities, and often that’s as a result of one parent’s drive to be the expert, which seems to cause one parent to fulfil more burden of care and that fosters some level of resentment or sense of loneliness towards the other one.

Jillian: There are some scary statistics out there around familial breakdown in this context, and it is something which there are so many factors at play, but it definitely seems to be quite widely recognised and definitely a problem.

In terms of the time that people have to spend on liaisons with the research community and the clinical community, that could bring us quite nicely back into a question for you, Karen, about what kind of information the GenROC study is looking to collect from families, can you tell us a bit more about that, please?

Karen: Yes, absolutely. As I said before, I’ve been very conscious of the sort of lives that our families are living, and listening to Lindsay, her story is very reminiscent of so many others and yours, Jillian. So I know families have about a gazillion hospital appointments, their children are often also very, very ill intermittently or a lot of the time, then they’ve got school stuff to deal with or they’ve got EHC plans to try and fight for. It’s more than a fulltime job in itself just being a parent of a child with a rare disease and it’s hard work, so me asking them to do anything else is asking a lot.

Luckily, I find, with the families I work with, who are universally wonderful I should add, that they are actually just really enthusiastic anyway about research for their child’s condition, and that’s because there isn’t enough information out there, so it’s relevant and important to them. But because they have no time at all, and any time they do give is their own personal time when they could be finally putting their feet up and watching something on TV, I have to make it as low effort as possible.

The questionnaire is all online, using a user-friendly and interface as we’ve been able to develop. It’s very user-friendly, it takes 10-15 minutes to complete; they can come and go from the questionnaire as well. We only ask for one time point at the beginning, which is all the sort of stuff that most parents will be able to tell you off the top of their head as well, so they don’t have to go looking for loads of information, apart from a height and a weight. Then later down the line we’re going to ask for a second questionnaire, it’s in the process of being finalised and again that will be the same amount of time, very easy to do, online, at their convenience. It was co-produced with the PPI group, they’ve tested it for me, I’ve had really good feedback and I’ve asked parents who are in the study as well for feedback. Everyone tells me it’s not too difficult or burdensome for them to do.

The secondary questionnaire has been very much informed by conversations with the parents that I had as part of a nest of qualitative interview study in GenROC, and that has driven that secondary questionnaire quite differently to what I thought it might be when we first set up the GenROC study. At the beginning I thought it might just be: have things changed for your child? Can you give us a bit more clinical data? But actually I realised that probably I will still gather that information, but they probably won’t have changed that much within the timespan in the study because it will only be a year or two after they completed the first questionnaire, and actually I realised that it would be much more useful to look at the impact of the genetic diagnosis, look at how they’re accessing services within the NHS, what sorts of services they are accessing, Impact on the family and also looking at priorities for families.

So families have talked to me about what their priorities are in rare disease, both in service provision but also in research, and I really am a very strong believer that we need to be given the limited funding, we need to be doing the research that matters the most to the families, not to the researchers. What do families actually want us to look into? Actually, do they want us to be looking into behaviour and what strategies work best for example, rather than something else very medical – what matters the most? And so that’s going to be a specific question in that secondary questionnaire, really trying to identify what matters to families the most and then how that can be translated into clinical research in the future. So I’m really interested to see what’s going to come out of that.

Lindsay: I think that sounds brilliant, Karen because I think historically there’s been a significant kind of absence of patient voice in rare disease research and development, and knowing that 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 a much greater impact on the care and treatments for patients in the future and certainly it makes endpoints more relevant to families as well.

Jillian: What kind of outputs are you going to be looking at?

Karen: The height and weight, the reason I’m asking for that is really because we are trying to work on growth charts for children and that’s because growth charts for children with rare conditions don’t exist by enlarge, there are a very, very tiny number of rare syndromes or conditions that have their own growth chart. The problem is that most children with these sort of rare conditions that we’re talking about are either quite small or quite big, and the problem is that the paediatricians look at their growth and they go, “Oh well, you’re much bigger or much smaller than other children your own age, what shall we do about that?” and particularly the little tiny ones it causes lots and lots of concern, so quite often these sort of growth parameters mean that the paediatricians do lots and lots of tests or put feeding tubes down, or add lots of calories, so it can be quite invasive and interventional actually that sort of growth parameter.

But actually, sometimes that’s because of the genetic condition and no matter how much feeding you do it’s not going to change anything. The difficulty is we don’t know that for certain, and actually we need good growth charts where paediatricians can make that call, and conversely sometimes a child actually does need investigating and the paediatrician puts it all down to their genetic condition, and that’s why we need these growth charts. So GenROC is aiming to gather growth data from all these children and then we’re going to work closely with Decipher, which is a website that was developed through the DDD study, which already holds lots of data from that study, so we’re building on the power of that study and we’re going to be generating growth charts for all of these genes.

We’ve developed a new method for producing growth charts for rare conditions where you’ve got small numbers of patients – that was never possible before, so we’ve already proven now for four conditions we can, so the next stage is using all the GenROC data, putting it into Decipher and coding it in. So, 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.

Jillian: And is that something which will be shared with the families individually?

Karen: Really great question. I hadn’t planned on sharing the growth charts individually with the families, but that’s something I can also go back to my PPI group and discuss with them about whether that’s something people would want, and also I have a newsletter which goes out every three months to the families, so I can certainly ask that question actually directly. It’s going to be widely available, the growth charts, we’re going to make sure that they’re accessible to paediatricians and clinicians etc. but in terms of output to the study, definitely the growth charts, we’re also hoping to have other clinically useful outcomes depending on the different genes that come into the study. We essentially have a cohort of children with rare conditions, everyone puts everything down to a specific genetic condition but we know that there must be other factors at play that influence how children do.

And this is a really unique thing we’re trying to do with GenROC actually, looking at aside from that genetic variant, that alteration, what other factors are influencing how children are doing? Because some of those might be modifiable, you know, or some of them there could be things that could be put in place to help improve outcomes. So I’m quite excited about that as well, because that’s quite new and novel and not really been thought about in this context before, so that will be an output.

And the other output is something that I’m working on with Unique, which is the rare disease charity who has worked with us on GenROC from the start, and they are involved in our PPI as well and that is going to be looking at a template, calling it a report at the moment, it’s in very early days, but something that parents will be able to hold, it’s going to have lots of drop-down boxes that can be tailored and modified for individual patients and children, which will be a bit of a guide that they can give to clinicians, professionals, education, telling them about their condition but also telling them on an individualised basis about what needs to be looked for in the future. Because parents tell me they are fed up of having to tell everybody about their child’s condition constantly, all the time, over and over again. So what the point of this output would be is to try and ease that burden a little bit. This is very early stages but we’re going to involved parents all along the way.

Jillian: And is that something which builds on the hospital passport idea that we’ve seen emerging around the world over the last few years where parents can start off telling their child’s story on their own behalf?

Karen: So, it’s come from my own lived personal experience of being a mother of a child with autism and I haven’t really spoken about that publicly before, so it’s something I’m saying for the first time. I have a child who has autism and I have had to navigate things like a DLA application form.

Jillian: That’s Disability Living Allowance.

Karen: Yes, exactly, which is a horrendous form, it’s the most horrible form to complete, probably apart from an EHCP plan form but it’s a horrible form to complete, it’s quite upsetting as a parent and it’s also got millions of boxes that you have to fill in. But one of the things that really, really helped me when I was completing that was a charity who had come up with lots of drop-downs that you could select from that might be applicable to your child to help you complete this form. And so it made me really think, “Well, could we do something similar for our children with genetic conditions but come up with lots of dropdown options that might apply to their child in all sorts of different areas?” And that was the inspiration, it was that, and doing the qualitative study that I’ve already done with parents of children in GenROC who were telling me about how fed up they were of having to constantly tell everybody about their child’s condition over and over again.

Jillian: Yes, that’s probably very helpful to empower families to use standard terminology across the different families because my own son has epilepsy as part of his condition but actually trying to describe what his seizures look like I’m not sure I’m using the right words to fit the right boxes to fit them into the right categories with the neurologist. So that level of standardisation is something that we definitely need embedded into the system in order for more people to be able to use this data more effectively, so that sounds very helpful.

Lindsay, coming back to you, what are you hoping to get out of this study, or what are you hoping this study will do on your behalf for the world? What motivated you to take part?

Lindsay: I think I would like to see all of the aims of the study realised and for the study data to be used to inform the development of standards of care for a wide range of conditions, those included in the study. I think it would be great if that information, as Karen said, is available not only to the participants but also to children diagnosed with those conditions in the future and also it’s an opportunity to consider themes that are identified across the disease groups as that can also help inform future research and look at investigations into the mechanisms of disease and where actually therapeutics could treat maybe more than one disease at a time and increase potential for basket trials and early access programmes – thank you to Dr Karen Low and her team for conducting the project because it included a comprehensive list of rare diseases, it really does give parents and patients an opportunity to have a voice and to contribute, which is empowering, and it gives them a little bit of autonomy as well over their direction that science and research goes to.

Jillian: Fantastic, thank you. Karen, can you tell us a little bit about the timeframe for the study? I realise that we haven’t really touched on that so far.

Karen: Yes absolutely, I’m aiming to recruit 500 children as a total. We’re open at 22 sites across the UK. Coinciding with this podcast actually we’ve opened a second door for recruitment, so the way we’ve recruited so far has been through clinical genetic sites, which is the way we’ve done these sorts of studies in the past, like the DDD study. The problem is that that relies on clinicians identifying eligible patients and clinicians are very, very busy in the NHS. I have worked closely with Unique who have been doing a lot of publicity and the genetic alliance have done publicity as well for the study, so that’s been one way of identifying eligible participants. And also just parent power through social media has been amazing.

The second way we’re going to recruit, and this is going to happen very soon, is through Genomics England. So, we are going to trial a completely novel way of recruiting to research through Genomics England and that is for Genomics England to identify eligible participants for GenROC and this would have been through the 100,000 genome study and then they’re going to send them invite letters, inviting them to take part. So that’s the next phase of recruitment, I think if we have more than 500 then that will be great too, we’ll be able to include those comers too, so that’s not a problem.

But we don’t know whether this will work or not in terms of a way of recruiting to research, this is completely new for Genomics England and I’m a bit of a guinea pig if you like through the GenROC study, but I was quite willing to be that guinea pig because I thought it might increase access. So there will be some parents who have not been told about GenROC who have not heard about it, and who would love to take part, so I feel like this is the way of really widening that net as wide as possible.

Jillian: I think that is a challenge isn’t it, especially in rare disease – there’s no point doing a public broadcast about an initiative because you’re going to hit so few of the people that you’re interested in, so actually how you access the community is the first challenge and I’m really pleased that Genomics England will be able to help you there because I think that is a very useful route through.

I think it will probably be quite reassuring to quite a lot of families who were on the 100,000 Genomes Project who have got a diagnosis of one of the conditions that you’re interested in, and are now perhaps subsequently in the fallow period after you have a diagnosis, wondering what happens next, so I can imagine it might be quite good news for some of them at least that they are now being invited to do something further.

And the reason that you’re building forward and you don’t want people who are currently in the deciphering developmental disorders study is because you’re already using their data through another source, is that correct?

Karen: Exactly. So absolutely, I don’t want anyone to feel that I don’t want them, that’s really not the case. I do want them but we have their data already from Decipher, so we’re building on the DDD data already, so they’re already contributing which is just the beauty of it, because that’s what we should be doing in rare disease, we should be building on previous research because you know, you don’t want to be trying to reinvent the wheel.

Jillian: Agreed. So if someone is listening to this and has a child with a rare developmental disorder and they are interested in finding out more, what are the steps they need to take?

Karen: If they Google Bristol University, GenROC, they’ll come straight to the webpage and everything is on there. There’s a link that they can sign up, the patient information leaflet’s there, the eligible gene list is there, all the information they need, including our email address.

Jillian: And is there an upper age limit for recruitment?

Karen: Yes, children have to be under 16 and that’s because once they get to 16 many of these conditions have associated learning difficulties, and it’s just very much more complex to try and recruit young adults, young people, with learning difficulties and given it was a cohort study we felt it was going to be too difficult at the moment.

Saying that, I have a huge interest actually in how these conditions present in adulthood, and I’m actually conducting a much smaller study at the moment in KBG syndrome, looking at adults, and so I hope that my future research career will allow me both to follow-up the children in GenROC, so that would be my vision but also to be able to take this forward for other adults with rare conditions, that’s my aim and goal in the medium to long-term, so watch this space for that.

Jillian: That sounds very exciting, thank you.

Lindsay: I think I would like to say to Karen that I really like the sound of the idea of following patients up into young adulthood and adulthood, as you said, that is definitely a kind of an unknown area in lots of the rare diseases, especially in our condition, SLC6A1, it was mutation and the disease was only really discovered in 2015, so it is fairly new and we have very, very few young people and adults coming through and being diagnosed and connecting with the rest of the community. So, being able to understand the trajectory of conditions better and especially conditions where actually the presentation it’s quite a spectrum, and so the long-term outcomes for people with SLC6A1 can look quite different, so it’s good to collate more information about that I think.

Karen: I think it’s really important, so that’s definitely where I’m looking to for the future with GenROC and more widely, I think it’s just something I’m really interested in and has huge relevance for parents and families.

Jillian: Well, I think we need to wrap up there but thank you both very much Dr Karen Low and Lindsay Randall for joining me today as we’ve been discussing the GenROC study, and how the study aims to improve understanding of how rare genetic syndromes affect the way children grow, their physical health, their development, but also how the patient and parent communities can work more closely with researchers to end up delivering something which is of a huge benefit to everybody.

If you would like to hear more about this, please subscribe to ‘Behind the Genes’ on your favourite podcast app. Thank you for listening. I’ve been your host, Jillian Hastings Ward. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.

Dr Rich Scott and Adam Clatworthy: Reflecting on 2024 - A year of change and discovery

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, genomics, can be a way in to finding them, but doing that at the right pace, and very much in a research setting.  That’s been a real, a moment, I think there’s been so much work on the path to it, but it’s right to sort of celebrate these staging posts on the way.  We’re early in the programme, there’s lots to do, lots to work through, lots of evidence that we’ll accrue, but it’s really exciting to be at that staging post. 

Adam: No, absolutely, and from my side, I think seeing all of the media pick up for the Generation Study launch, you could really see the excitement in the wider kind of community.  Seeing it shared on social media, obviously those part of the 100,000 Genomes Project, seeing things like this.  It’s like they can see the tangible outcomes of all the work that they’ve done as part of that initial project, and seeing how those learnings are then taken onto this new study.  So we’ll now hear a clip from earlier in the year from Louise Fish, who is the former CEO of Genetic Alliance UK, who shares her thoughts on the potential of the Generation Study. 

Louise: The Generation Study is looking at 200 conditions and whether it’s possible to screen for them.  And for all of those 200 conditions, it’s a really exciting opportunity to see if we can learn more.  Both about the potential to understand and develop treatments early, but also just about the chance to understand the natural history of that condition so much earlier than we do at the moment.  And I think that’s it, it’s that understanding the natural history of the condition really early, and understanding how a family can be helped, through all aspects of the condition, which is giving people most excitement I think, alongside the potential to develop treatments. 

Adam: So now, let’s look back at the priorities for Genomics England for 2025.  Now, Rich, would you like to just take us through some of the things you’ll be focusing on next year? 

Rich: Yes, one of the things that we’ve been doing this year, but also actually in the year before, is really looking to the future.  And saying, where might we be in terms of genomics really living up to the impact it could have, if we collectively, in the UK and working with international partners, sort of get things right?  And that’s very much about balancing the realism of where we are, and the impact we’re already having, and being proud of that, and then getting that same sort of ambition and realism casting to the future.  And I’d say, I think there are two really broad themes.  I think the first thing is, we’re enormously proud of the impact we’ve had already for families with rare conditions, and people with cancer, and that impact will continue to grow in the coming years, in those areas.  And in the next few years, that’s where the biggest impact of genomics will continue, and the rare disease programme we have thinking increasingly about how we support the generation of evidence and pathways that lead to rare therapies.   

So building, getting better all the time at finding diagnoses, which is still a long journey we’re on, and continuing that work.  Increasingly thinking about how we can support therapies, and in cancer, again, playing a better role in cancer, both by driving efficiency in diagnostics, and efficiency in identifying where therapies enabled by genomics can be targeted.  And we see lots of different examples of that, clinical trials is a big area where we hope to have more impact in the future, but also thinking about some of the novel therapies that are there, both for rare conditions, but also, for example, the cancer vaccines.  And I think we’re uniquely placed in the UK, because of our partnership at Genomics England with the NHS, and the broader science ecosystem, to have that impact.  So that’s the sort of like continuing very much where we are, but really pushing those boundaries. 

And then also, if we look to the future, to say, what role could genomics play?  And we, as you know, our vision at Genomics England is a world that everyone can benefit from genomic healthcare, and I think that plays out in a couple of ways.  Firstly, 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 based into all of our work.  And then also, to say 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.  And as we set out where we think what evidence is needed and where we need to learn what the digital infrastructure that we build and others build, need to build that to support that, we look across a few different areas.  But really you can see genomics playing a role across the lifetime, in different places in different roles.  

To pick one really powerful example is something people often refer to as pharmacogenomics.  Which is a medical term for what boils down to look at a person’s DNA sequence, that’s the genomics bit, and making decisions based on what drug to give them, what drugs to avoid, or perhaps what dose to drug to give them.  Based on, for example, the desire to avoid adverse drug reactions that people might be at high risk of, and you can identify that risk looking at the DNA.  That is one example of genomics playing a role in being increasingly sort of preventive, getting away from disease, getting upstream of disease arising, or harm arising.  And there are other opportunities in common disease as well, sort of casting forward to what that impact might be, and we feel that genomics could play a role, really broadly, across healthcare, in probably as many as half of all healthcare encounters.   

But what we need to do over the coming years for that to potentially be the case is we need to build out the evidence, and we also need to understand what digital infrastructure we need, to make that a possibility.  So that the information is there in simple format, for patients and the public, for their GPs, for their pharmacist, for people in any speciality in hospital, not just sort of rare disease clinics or in cancer, as we are at the moment.  And so very much we’re thinking about the programmes that we and others could run to ask some of those questions, to think about what we need to build out.  We feel that the UK’s uniquely placed to develop that evidence, so that we can make the choices about how genomics is used, and so we can be ready to embed it.   

And it really aligns with that shift that we see and we hear, for example, in government being talked about, when we’re looking about sort of the shifts that the NHS sees as essential.  You know, increasingly preventive, increasingly digital, increasingly in the community, and that point of sort of getting upstream.  And genomics is going to be an important part of that.  And we at Genomics England are really excited about the role that we can play, whether it’s through the digital infrastructure we build, whether it’s the programmes that we run to develop the evidence.  Or whether it’s through the ethics and the engagement work, the work with the Panel, and the work with the wider public, to understand how we might develop this evidence, what people are comfortable with, what the expectations are.  And I think that, pulling that together is complex, it’s really exciting to think about how we do it.  I think we in the UK are uniquely placed to take advantage of that. 

Adam: That’s great, and I think the pharmacogenomics piece is fascinating.  I mean, you hear many stories of people having adverse reactions to certain medications, and you wouldn’t even think it’s something that may be linked to their genetic makeup.  It’s so important that we take people along that journey, around what the benefits are, the ethics, to make sure that people really understand the journey that we’re making and what the potential impact could be.  Whilst there’s lots of amazing new areas to develop into, a key focus for us on the Panel is really continuing to demonstrate how the 100,000 Genomes Project participants continue to have an impact, and they’re helping shape a lot of these developments.  So they generously donated their data, it not only helps Genomics England develop the systems and services that now benefit many families, but it also continues to drive that scientific and technological enhancement.  So it wasn’t just about reaching that 100,000 genomes, that project was really the starting point, as it were, it’s not the finish line, it laid the groundwork for a lot of these developments.  So it’s about how do we focus on maximising the benefit for those participants over their lifetime, not just at that one point in time.   

We know genomics is evolving so rapidly, what you can glean from a genome today is far more than what was possible in 2013.  And we know the Diagnostic Discovery team is continuing to analyse the data for participants in the project based on these new advances, the team led by Suzi (Walker), who’s doing some amazing work there.  Using all the latest tools and enhancements, just to make sure that those participants are really benefiting from that learning.  So, we just need to make sure we stay close to that wider community, and just ensure they’re not forgotten, that’s really a key north star for us as the Panel.  And something that we’ve been pushing is better ways that we can help to communicate the ways that you're celebrating these successes, providing regular updates on research progress, offering personalised reports based on the latest findings.  And it’s all about providing them with that hope.  Some people may never get a diagnosis, but it’s about giving the hope that one day they might get that phone call out of the blue, so it’s about giving the hope that those possibilities are out there for others.   

So we’re now going to shift gear onto hearing from Shaun Pye, who is the father of Joey.  She was diagnosed with DYRK1A syndrome, which is a rare chromosomal disorder, which causes a degree of developmental delay or learning difficulty, at the age of just thirteen.  In this podcast episode, Shaun and his wife Sarah told us of their journey to Joey’s diagnosis, and how their role in writing the BBC television comedy drama series, There She Goes, has helped to shine a light on the rare condition community. 

Shaun: Then the opportunity came along with 100,000 Genomes, and we signed up immediately.  And then that, they did that, and it was a few years before that went through the system, and then we had, out of the blue really, we were asked to go and see a geneticist, and we had no idea that this is what it was.  I honestly thought it was just a routine sort of, we’ve got a few more theories or something, and she just said, “We’ve found out what it is.”  And it’s like, that moment is, well, we tried to describe it in the TV programme, but it is quite hard to describe what goes through your mind, when after thirteen and a half years somebody suddenly says, “Oh, by the way, that thing that happened with your daughter, we’ve worked out what it is.” 

Adam: So here, Rich, did you want to provide some updates around future progress, particularly in diagnostic discovery and expanding the research? 

Rich: When we’re looking to the future, we’re looking sort of in two areas.  How we can build the impact we’re having today for families with rare conditions and cancer, and that very much includes the participants in our programmes, 100,000 Genomes, those through the NHS Genomic Medicine Service, who joined the National Genomic Research Library.  And we’ve seen, I think the number that I’m most proud of at Genomics England is that number of diagnostic discoveries returned to the NHS, which has just hit the 4,000 mark.  And for those less familiar with the terminology, essentially what that means is where either researchers or the internal team at Genomics England have identified changes in the genome data, that with new knowledge, often with a fine tooth comb, it’s considered likely that that is the answer to the cause of the rare condition in that person in the programme.  So that’s 4,000 of those returned to the NHS.   

And that tells you a lot about where we are for families with rare conditions, and I think there’s two points here.  The first one is, we’ve got a long way still to go to do what we want to for families with rare conditions.  I’m a doctor and still see families in my clinic once a month at Great Ormond Street, even with the incredible advances we’ve had over the last particularly 10or 15 years, with the changes in sequencing and analysis, we still find an answer for the minority of families.  So that number is growing, and we’re really proud of how much better we’ve done, and there’s a long way left to go.  And the really critical thing is designing a system which we’re so lucky with in the UK here, where we can continue to learn.  And that’s not just for learning for the knowledge of people who might encounter the health system in the future.  It’s to learn for those people who’ve joined the National Genomics Research Library, who’ve already trusted us to be the custodians of their data, and to do better in the future.  And that’s what our diagnostic discovery work really aims to do. 

And sometimes that’s about new gene discoveries.  So all the time new things are being discovered each year.  And if you look at the DNA code, if you like, boil it down very simply.  99% of it is what we call non-coding DNA, I’ll come back to that, about 1% is the genes, which if you like are sort of the books in the library of the DNA, overall DNA code, that we understand relatively well how they’re read by the body.  The bits in between, it’s a bit of a funny, well-spaced out library this one, that’s the 99%, actually we’ve had very little understanding of most of that code in between.  But we’re beginning, and particularly this year, to gain an understanding of how we might interrogate some of those pieces.  And not all of the answers lie in that non-coding DNA, there’s lots of answers still left in genes that we don’t understand well.   

But one of the examples I mentioned earlier, and in fact the thing, the single discovery I guess which I’m most proud of having happened in the National Genomic Research Library is this discovery of this non-coding region called RNU4-2.  Which is a funny, like technical series of letters and numbers, but basically it’s a very small patch of the whole DNA code.  Where this year, scientists discovered actually about 60 patients in the families in the National Genomic Research Library where that was the cause of their child’s developmental disorder.  Actually, that knowledge has really rapidly spread across the world.  So I actually saw on social media at the weekend, from one of the scientists involved in the discovery, that the family support group that’s been set up for what they’re calling ReNu syndrome, which I think is a lovely name in itself, speaks to that word hope that you mentioned, Adam.  There are now 248 members of that group, and that’s how fast that knowledge spreads across the world. 

And what we’re doing is thinking how we can support those discoveries more broadly, and non-coding DNA is one of those areas where that growth is, but it’s not the only one where we’re looking to support things.  But it’s so exciting, and I think it gives you a sense of the scale of progress that is left to make.  And I think a really important point is that remains a really important area of our focus, it’s not about moving on and looking just to the future, but we need to keep working for the families who are already part of our programmes. 

 

Adam: That’s incredible, that 248 members in such a short space of time.  And I love the ReNu name for that, I agree, I think that’s a fantastic way of positioning it.  Earlier this year, we heard from Lindsay Pearse, whose son Lars received a diagnosis through that groundbreaking discovery of the genetic change in the RNU4-2, or ReNu gene, which was made possible by whole genome sequencing.  She told us what the diagnosis meant for their family. 

Lindsay: This feeling that, like, we’ve been on this deserted island for eight years, and now all of a sudden, you're sort of like looking around through the branches of the trees, and it’s like, wait a minute, there are other people on this island.  And in this case, actually there’s a lot more people on this island.  Yes, it’s very exciting, it’s validating, it gives us a lot of hope and, you know, it has been quite emotional too (laughter).  And also, a bit of an identity shift, because I spoke earlier about how being undiagnosed had become quite a big part of our identity, and so now that’s kind of shifting a little bit, that we have this new diagnosis, and are part of a new community. 

Adam: You talked about it there, Rich, I mean, it’s been really seen as a success story for the whole genomics ecosystem, especially the speed at which it all came together.  From the conversations I had with some of the individuals that were involved in the study, from the date of seeing the first findings in the lab meeting to a polished pre-print going live, was exactly 47 days, which in science terms is less than a second.  So that’s how they positioned it to me, incredible.  And you’ve just said there, they set up this support group earlier this year, and already got 248 members, which is incredible.  The impact on families is significant, the mother touched upon it there.  I mean, for many parents there is that relief that it wasn’t something they did during pregnancy, but instead, it is a chance occurrence.  For some, this knowledge means that they can make important decisions, choosing to grow their family, for example.  And it really ends that diagnostic odyssey that many families face, providing answers and potentially ending unnecessary testing that their child is going through. 

But I think, and I can talk from personal experience here, that the largest impact is really being able to connect with other families and building that community, you cannot really understate that.  If I look at our own experience of getting a CRELD1 diagnosis for our children, the first time we didn’t feel alone was when we could find that community.  We can support each other, we can learn from each other’s experiences, and really also drive forward further research into that condition through advocacy.  So, I remember seeing that post on the Facebook page, about that RNU4-2 discovery, and this was before I’d even started in the role at Genomics England on the Panel, but you could really feel that excitement and the relief that they had.  And they mentioned that the official paper only had 36 other people worldwide, they found this little Facebook group that they created with five families in, and in the space of, what, 6, 7 months, they’re already at 248.  That’s all people that understand what they’re going through. 

And it’s really hard to describe, it’s like finding your family that you’ve never met, people that understand, and they really get what you're going through.  And being able to share tips, advice, learnings, and things that everyone’s going through at different stages in their child’s life.  So, I really don’t think you can talk highly enough of that, that community aspect, and that’s just been amazing to see.  And, look, this new era of research into the role of non-coding RNA genes, it really may open more opportunities for diagnoses for patients, participants potentially leading to hopefully more breakthroughs in the year ahead. 

So now we’re going to move on to why it’s so important to engage patients and participants in the genomics world.  So, we’ll now hear a clip from Helen White, who is the Vice-Chair for cancer on the Participant Panel.  Now Helen and I have been working really closely together as Vice-Chairs in this interim leadership role, to really ensure that we continue advancing the Panel’s strategic initiatives while we recruit that new Chair.  So it’s been amazing learning and working with Helen.  In this clip, she discussed an important topic that’s been very much top of mind of the Panel, which is the importance of involving the patients and public in genomics research. 

Helen: I think, you know, as patients, members of the public, we’re eager to get on and for change to happen and things to be better, but it’s, yes, a big, big process.  But also, good to hear that you talk about it being a collaborative approach, it’s not just Genomics England, it’s the NHS, it’s members of the public and patient voices, it’s other organisations working in partnership. 

Adam: Now I think we all recognise the importance of engaging patients and public to ensure diverse communities understand the benefits of genomics, and actively involving patients and participants in the research, to make sure that they’re including the perspective of what matters most to them.  

Rich: I mean, it goes back to the thing that we really see as central to the value that we at Genomics England can provide.  So we increasingly think of ourselves as a data and evidence engine for national scale genomics, and I think a really important to call out there is that evidence is broad.  And part of that evidence is about public expectations, public preferences, and patient preferences.  And if you think about the big things that we do and where we bring that value, and bring that data and evidence engine role, is, you know, firstly in the digital infrastructure that we build and the data that we hold and present to our various users.  Secondly, it’s in the evidence that we distil from that, and very much thinking about part of that being evidence in and around, including that piece on what people expect, this isn't just about hard science and health economics, this is an equally if not more important part of that.  And then thirdly, it is the third area of our focus is on that engagement piece, because that’s so fundamental. 

And I think you and Helen called that out absolutely right, about that being, that’s integral to the whole process, and it’s the beginning of any programme you need to start with understanding what the big drivers are, what the expectations are, and doing this very much together.  That’s one of the reasons we’re so fortunate to have the Participant Panel we do, in our Newborns Programme the Panel have been an important part of that design from the outset.  It’s also about broader engagement with different communities, people who currently don’t engage with genomics, because they’ve had no need to, sort of understanding that piece.  And I think we’ve definitely seen over time in health data research, but also research more broadly, where it’s quite easy for these things to be disconnected.  And that results in two things.  It results in research happening about interesting esoteric stuff, but not on the stuff that makes a difference for families.  And I think that’s really important, because researchers need to be directed in the resource limited world towards the things that really make a difference.  So that’s the first thing. 

And the second thing is, it’s very easy, with the best will in the world, for people to make wrong judgements about what people are or aren’t content with, and you need therefore to be absolutely transparent about what the research is.  Be really clear about what those questions are, and let people challenge you, right from the outset, so that we can design research studies, but also, the system as a whole, together in a way that everyone has a say.  Not everyone has the same view, but how we can develop a system that takes into account those things and gets that balance right.  This is about making a difference to people’s health outcomes, thinking about how we achieve that, while also balancing off all of the different views there are, is really important.  And that’s at the heart of it.  And it can be scary, because it’s right that there is that challenge out there.  And it’s one of the things that I think we’ve learnt at Genomics England, how important it is to be really open to that challenge, and to do that piece really early in all of our work, and have it there baked into our governance as well, for example, the Participant Panel. 

Adam: Absolutely, and I think you’ve summarised all the key areas there really well, in terms of the importance of that engagement.  And one other area I’d just like to pick up on is the impact it can have on the patients or the participants, simply by having that connection with the researcher, that’s doing all of the amazing stuff that for some of us, it’s really hard to comprehend.  But having that interaction and collaboration with them, it’s so important in terms of, again, I go back to giving you that hope.  And a real highlight for me at the Genomics England Research Summit was when Hannah, one of the members of our Panel, she came running over to us and she was just beaming.  And she said, “Guys, you’ll never guess what, I’ve just met the scientist who discovered my daughter’s diagnosis in the NGRL.”  And you could see that she was so excited, you cannot understate the impacts that can have on them as a family.  Like having that interaction and that personal connection with the person that really in some ways kind of changed their lives, in terms of understanding more about what that could mean for their daughter growing up, and how they’re managing the condition.  So, it’s amazing when you can see those highlights and hopefully we’ll see more of those. 

And it’s also really important that we get that diversity I think, as well, in that collaborative approach, just to make sure that it is equitable for all.  And that really brings us on nicely to the next topic, which is about how do we bridge the gap between those diverse communities, and make sure that we’re reaching everyone as best as possible?  So we’re now going to hear a clip from Sandra Igwe.  Sandra is a CEO and founder of the Motherhood Group, speaking about the Generation Study.  Now, Sandra spoke about the importance of building trust, and how it is vital to engage with a diverse group of communities in the design of research studies. 

Sandra: Every community’s different, and every patient is different as well.  And so that may require different focuses or different formats or different messengers for different groups.  And so we like to have people with lived experience from the community representing that, and also driving the uptake of consent as well.  But failing to engage diverse voices can lead to perpetuating inequalities in access and uptake.  So it’s really important to have representation, because the lack of it in research can overlook communities’ specific concerns and needs. 

Adam: So, Rich, did you want to talk about why it’s so important to have that diversity? 

Rich: Yes, I mean, it’s critical.  One, I mentioned earlier, our vision as an organisation is a world where everyone benefits from genomic healthcare, and that word “everyone” really resonates.  I think Sandra has been really an important part of the work that we’ve done over the last couple of years, particularly through our Diverse Data programme.  But I think one of the real challenges for us is how we make sure that that is something which is embedded across all of our work.  And that’s something that we’re really focused on at the moment, how we embed the learnings that we’ve had through that standalone Diverse Data programme into everything we do.  Because we’re absolutely committed to that, and I think that is engagement with the diversity of different groups relevant to each programme.  I think one of the real important things is that transparency piece about actually that it’s hard to achieve equity in healthcare, full stop, because of historical underinvestment in some of these areas.  And I think being clear with people about that is a really important step, and then talking really practically about why it really makes sense to take different approaches. 

And so one thing about our programmes and how we think about the future overall, if genomics is going to make a difference to more than half of healthcare encounters, it needs to be something that across all communities, and across the large majority of people in each of those, that this is something that they want to be part of.  Because it’s going to make a difference for them or their families or something they really buy into.  And that’s why this isn't just about thinking only about specific programmes where this is a question, it’s about making sure that we’re designing a system, developing the evidence that is really broadly applicable, and continues to learn.  Because we know that what we learn today is hopefully an improvement on where we are, but we continue to learn and learn and learn.  And it’s about creating a system that does that, and does that equitably, or as equitably as we can. 

Adam: So we’re now going to hear from Moestak Hussein, who works to build and embed cohesion, inclusion, and social justice, in her role at Bristol City Council, in public health and communities.  Moestak talks about the value of co-production, and how this can help to build trust with communities who have historically been underserved or mistreated. 

Moestak: If we talk about co-production, true co-production is really creating a power balance where there’s no hierarchy, it’s an empowering model.  It empowers both the researchers or the person that comes in, but also the communities that participate, and you all start on the same level, on the same outcomes and the same goals and aims that you want to achieve. 

Adam: So, if I look at that from our perspective on the Panel, I think co-production in genomics research, so using participant data in the NGRL, is certainly what we’d like to see much more of.  To ensure that research is not only relevant to its intended audience, but also aligns with broader democratic principles of citizenship, accountability, and that transparency as well.  But look, we have to be realistic.  Some genomics research projects are not going to lend themselves to meaningful patient and public involvement in the early stages, but it’s really important later on in the research pathway, if the findings identify a patient population who might benefit from that research.  At the moment, involvement of patients and participants, carers in research, is really not great, in terms of the researchers using the NGRL.  So, in conversations what we’re hearing is they’re saying, “Well, we don’t know how to do it, we don’t know what steps we should take.”  Or “We don’t think it’s relevant because we do this particular research.”   

But really, our view is that some PPIE, or patient and public involvement engagement is better than none.  Some may not be relevant for all stages of the research pathway, we’re not really seeing enough of that happening at the moment, and some papers are even being published without any context of the participants’ lived experience at all.  Which can actually be quite frustrating, if you're that patient or parent, and you see a paper published, and you think, well, actually, why didn’t they reach out to us?  Just to understand a bit about the symptoms that we’re experiencing, what are the challenges that we’re facing, just to really add that important context.  So, I think there’s certainly an opportunity for us on the Panel, certainly for Genomics England, to be that kind of guiding light for those researchers.  Whether it’s providing them with researchers, research papers, or a hub of patient advocacy organisations that are already connecting those patients with researchers.  It’s all about signposting them the relevant information, so I think there’s certainly things we can do there. 

And it really fits in with the bigger engagement piece.  So, whether there’s a landing page or a dedicated website that shows them, where do they go, what are the steps that they can take, what’s the best practice, what’s worked well for another researcher, and how did that lead to really great outcomes for the families involved?  That’s where I think we can all play a part in guiding them on that journey, rather than it just being a case of, they’re not doing that patient and participant engagement very well, and kind of criticising it.  Let’s reach out to them and say, “Look, we can help you and guide you on that journey.” 

Rich: I really agree with the need to make those connections happen.  One of the things I think that is often missing is just a confidence just to crack on and do some of this stuff.  And I think, actually, looking at the ReNu syndrome experience, that was work that was swiftly done.  Scientific at the beginning, the initial publication put out there so that people could understand, and was quite medical by necessity, in terms of the speed of getting information out there.  And then very quickly, and quite organically, patient support groups have formed, and also, the scientists are working with that group.  I had a really interesting conversation with Sarah Wynn, who’s the CEO of the Unique last week, about how some of that has played out, how the role they’ve played in facilitating some of that.  And some of it just comes down to sort of really simple things, and working through how you can set up Zoom or whatever meeting, for people to learn about the condition.  And how you preserve anonymity, where that’s appropriate, but also allow people to have discussions about their loved ones where they want to, etc. 

So it’s partly just about giving people the space and the confidence to get on with some of these things.  And as you say our, one of the things we at Genomics England are quite thoughtful about, and I think it’s a really good topic to continue talking to the Panel about, is how we get that balance right.  Where, actually, us being a connector and, as you say, signposting useful resources or ways of doing these things, just to break down some of those barriers.  Because almost always the research groups, when they discover something new, this is really new territory for them, and they’re often nervous about doing the wrong thing.  And so it’s about breaking down some of that anxiety actually I think. 

Adam: Yes, absolutely.  In our case, with our condition that we’re advocating for our son, we’ve been working with a researcher.  And it’s almost on us as well just to kind of share our story with them, and making them feel more comfortable to ask us questions and be very open and transparent about the more we can share, the more that can hopefully benefit their research moving forward.  It’s very much a two-way thing as well, but I like what you said there about having the confidence just to kind of reach out and start those conversations, and have that starting point. 

Next topic, we’re going to look at some of the innovations that are on the horizon, that we’re seeing in the world of genomics.  So, Rich, do you want to take us through what are the most exciting things that you're exploring at the moment?  I know we hear a lot about AI and the technological aspect, so why don’t you take us through some of those? 

Rich: Yes, so I guess this comes back to that question where we’ve been looking forward, you know, where might genomics be impactful and making a real difference to people’s lives, to helping us have a more efficient healthcare system in the future?  And I think part of that is about this general shift.  You know, genomics technology, we just take for granted now how much it’s shifted, how it’s within the means of the healthcare system to generate genomic data.  And we’re really fortunate in this country because of the digital infrastructure that we’ve been able to build together with the NHS, that opens up a lot of these questions.  And it’s just extraordinary the time we’re at in genomics, so almost take those two things for granted, which we should never do.  The change in genomic testing technology, which continues to advance, and secondly, thinking about the digital infrastructure, like the nuts and bolts of what we’ve got, and the ability to safely store and reuse and analyse some of that data at scale. 

And point at two big things.  Firstly, genomics enabled therapies are changing a lot.  So, our understanding, our ability to make a diagnosis, or understand what’s different about a cancer, for example, mean that in various ways it’s becoming feasible to do more tailored therapies.  Where knowing that, the genomics nitty-gritty of that condition, helps you tailor that, or create sometimes even a bespoke personalised, truly for that one individual, therapy.  And in rare conditions we see that with the so-called N=1 therapies, but also with gene therapies and so forth.  And in cancer we see that with the cancer vaccines, for example.  So that’s an enormous area of change, and one of our responsibilities is to support that sort of research, to help identify people who might be eligible for trials or treatments.  But it’s also to work with the ecosystem to think about how we can help support the generation of evidence that means that those therapies can be affordable and so forth, on a scalable basis.  So that’s one really big area of excitement.  And we see our Rare Therapies Launch Pad being part of that, the National Cancer Vaccine Launch Pad, being part of that.  So that’s thing one. 

Thing two is AI and machine learning, and I think sat on alongside the sort of broader picture of saying, there’s a lot left to learn, there’s enormous potential in genomics in terms of playing a role in many different situations, not just in rare conditions, in cancer.  And we know doing that well, but also scaling it, making it really efficient, so that we can do that in a context of a really busy health service, one of the answers is making sure that we’re leveraging everything we can about the potential of AI.  And there’s lots of different ways in which that can be supportive, I won't list lots of them.  But one of the things that we’re doing at Genomics England and working with the NHS is thinking about the most promising areas.  And some of those are quite, like, down and dirty, if you like, so sort of saying, which jobs are there that we can use AI, if you like, as a co-pilot, alongside experienced scientists, to speed up their work? 

And we’re really excited about the role we can play in a few ways actually.  So the first one, back to that sort of data and evidence engine point, is helping organisations who have a tool, help validate it for use in the NHS, and say, “Does it perform to this standard?  What do we want to say about how it performs from an equity point of view?  And from a clinical safety point of view?” etc.  And making that leap from stuff that makes a Nature paper to stuff that lands in clinic is surprisingly challenging, and that’s one of our roles.  And we really enjoyed working with various companies and academics over the last few years on that.  We did some work recently with Google DeepMind, on their AlphaMissense tool, thinking about how we can think about that role that might play, for example, in speeding up the interpretation of rare variants that might cause rare conditions.  And there’s enormous potential in all sorts of different parts of the sort of end to end of genomics playing a role in healthcare. 

And then I’d also say one of the really important things is because genomics in many ways just needs to be part of healthcare and not be treated differently, we also need to recognise where there are questions we need to work through really thoroughly that are a bit more bespoke.  And one of the things that we’re really committed to doing, as we look to the future, is making sure that we can support on some of those questions that we really need to be clear on.  I’ll go back to that point on, what do we mean about making sure we understand how a tool is working, and whether it’s producing results in an equitable way for all different communities?  How do we understand that?  How do we explain what we understand about the performance of a tool?  How do we make sure that patient identifiable data remains non-identifiable if a tool’s been built, trained on data?  Working through some of those questions. 

But they’re really important for us to do, and we’re enormously excited about the potential, and we’re really committed to working through in detail how we can make that path to adoption safely and in the way that everyone would expect and desire as rapid as possible.  We’re just one step in that process.  But we really see a sort of important role for helping people who are producing various tools or various use cases, helping them prove them, helping them validate them, and making the system more efficient overall, but in ways that we really understand. 

Adam: That’s fantastic.  Look, not that I'm biased at all, but I can tell you that the AlphaMissense innovations that are being developed are shared a lot internally at Google, it has been seen as an amazing success case.  So hopefully we’ll see more on that moving forward.  But in the next clip, we’re going to hear from Francisco.  So Francisco is the Director of Bioinformatics at Genomics England, who tells us more about the application of AI and its benefits in genomics in healthcare. 

Francisco: So AI is already driving the development of personalised medicine for both research and healthcare purposes.  Now at Genomics England we are investigating the use of AI to support a number of tasks, for the potential impact in both research and healthcare.  In the context of healthcare, we are talking about AI tools that can support the prioritisation, the ranking of genomic variants to allow clinicians to make more accurate and faster diagnosis. 

Adam: While all of these innovations sound really exciting, 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 talked about that on the episode today.  I know that the panel has always encouraged 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. 

So, we’re going to wrap up there.  Thank you to Rich Scott for joining me today, as we reflected on key milestones for 2024, and looked at the year ahead for both Genomics England and the wider genomic ecosystem.  If you enjoyed today’s episode, we’d love your support.  Please like, share and rate us on wherever you listen to your podcasts.  I’ve been your host, Adam Clatworthy, this podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.  Thank you everyone for listening. 

Katrina Stone: What happens when I go for whole genome sequencing?

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.