Behind the Genes

In this explainer episode, we’ve asked Sasha Henriques, Director of Equity Assurance at Genomics England, to explain what we mean by the word equity in healthcare and genomics. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk . You can download the transcript or read it below. Florence: What do we mean by the word equity? My name is Florence Cornish, and today I'm joined by Sasha Henriques, who is Director of Aquity assurance here at Genomics England, and also has a PhD specifically looking at social justice in genomics. And Sasha is here with us today to tell us much more about the topic. So Sasha, I think with this topic, when it comes to discussing equity in healthcare, a good place to start might be by acknowledging that not everyone has the same experience with accessing healthcare or the same outcomes even when they do access it. Could you maybe tell us a bit more about why that is and what factors are at play there? Sasha: Hi, Florence. Thanks. It's a really interesting question because it's a really big problem. So, the reasons that we don't have access to the same things can have multiple different ways that we're affected, from where we're born, to the schools that we go to, to the education that we have access to. Lots of those things are outside of our control, and they're determined by the political landscape that we're born into, whether we're born in a rich country or a poor country, or a rich part of the country or a poorer part of the country. So those are kind of the structural things that might make things different. So, when we come to access healthcare, there might be different healthcare that's available to us. We might be able to negotiate the system differently because of what we understand about how healthcare works and what's available to us. And then there might be personal things about us that make those things more challenging, so the abilities that we have or don't have, both kind of the ways that we learn, the ways that we hear, the ways that we see. All of those things kind of change our access, so the way the system treats us, but also how we show up in the system are all things that can affect us when we come to engage with healthcare. Florence: And obviously, the topic of this podcast is equity, and we hear this word equity a lot, especially in conversations around healthcare and genomics. But could you explain for any listeners who maybe aren't quite sure what exactly equity actually means? Sasha: Yeah. So I think lots of times people hear equity, and they think it's just about fairness, and it's just about treating everybody the same way. But what equity does is that conversation, that question that you asked me about, like, why do people experience healthcare different, there are all sorts of places in our lives where we will have different access, different benefits, different ways that we can participate. And what equity says is that because we're all different in those different ways and we have different needs, different ways that we're discriminated against, and different ways that we're privileged, what equity means is how do we design a system, how do we offer something or do something that enables everyone to have the same outcome of that benefit? So for example, you could make a research leaflet really easy for everybody to access. And what that would mean is that everybody gains more access to that information. But if you are discriminated against because of the way that you read information or the way that you access information, that's not really helped you. So it's helped everybody, so we can move everybody along, and that's kind of what we would call equality. But actually, you don't all get the same outcome at the end. And what equity means is that we understand the different needs that people have so that when we look at where everybody arrives to at the end, that's where we see the benefit, rather than just making a change that's the same for everybody. Florence: Can we dive a little bit deeper into that? That difference between equity and equality. Could you maybe explain a little bit more about that specifically? Sasha: Yeah. I guess there are different ways that people illustrate the difference between equality and equity. And so equality could mean, for instance that everybody needs to get to a certain position, like from position A to position B, and everybody needs a particular bike to get from position A to position B. And so equality would be that we give everybody the same bike. So we make sure that your bikes have the same speed, your bikes are the same make, that your bikes are as new as each other, so nobody is given a worse bike than the other to get from position A to position B. But it might be actually that you've given this bike to somebody who isn't able to ride a bike because they have a problem with their legs, or it might be that you've given a bike of everybody's bike is the same size, but some people are shorter than other people. And so while equality means kind of treating everybody the same, equity actually means that we take consideration of the fact that we may need to treat people differently, so that they can get the outcome. So everybody can make the journey, but not everybody's going to make the journey in the same way. And equity is about what do we do so that people can all experience things and benefits in the same way, rather than treating everybody the same way. Florence: Mm-hmm. And do you think there are any challenges in equity specifically to the field of genomics? Sasha: Yeah. So I think that's a really simple explanation that I gave between the difference of equality and equity, and genomics is a really interesting point to show why that's a really simplified version of thinking actually what equity means. So when we think about genomics, there are a number of particular things about genomics and the history of genetics that make that equity conversation and the way that people's benefits and outcomes may be shaped really critical when we think about genetics. So one is, I spoke before about, you know, where you're born in the world can have a really big impact on what you're able to access and what you're not. And genetics is one of those things that kind of really changed the world but hasn't changed the world for everybody. And so the people who were studied, the people whose DNA was looked at, all of the things that give us the knowledge about how genetics should work, was largely done in only particular places in the world, so particular northern European countries, parts of the US, some of those studies have been done in Japan. So lots of the knowledge that we have around what genetics means for different groups and different people doesn't actually think about all of the people in the world. So when it comes to genetics, we're kind of using references and data that actually are already not equal with the people that we want to serve. So there's something like really embedded in the way that genetics works, that we're kind of already starting from an uneven landscape. And then genetics sits within healthcare, it sits within research, it sits within all these other places, which again, are affected by things like money and things like politics, political stability, geography, whether your country has legislation or policies for those things. So, I guess those are the kind of structural things that make genetics kind of different and more challenging when we think of those inequities that already exist. Florence: Yeah. Sasha: But then genetics itself is about finding information that, yes, is about you, but might also be information that we share with lots of other people, so people within our families, people within our populations. And so actually thinking about who has the rights over genetic information, how genetic information is shared, how the genetic information benefits everybody that it should, are other, like, really particular questions that come with genetics. So, there are all these different ways that the structure can build inequity into what we're thinking about genetics because of the history of where genetics has come from, but also the ways that the system kind of uses genetics, and the ways that genetics can be used against us. So I think it's really important, that conversation about equity in genetics, that it's not just about getting from place A to place B, it's about what is the road like? And what experience will you have? And when you get to the end of the road, what are people going to do with the information? Yeah. So actually, that really simple explanation that I gave can become really quite complicated when you think about something like genetics. Florence: And so you took on the role of director of equity assurance at Genomics England. Tell me a little bit more about that. What’s the purpose of this role? Do you have anything specific that you'd like to work towards or achieve? Sasha: So the reason that that role came about is because of some of those problems that I've mentioned, that you want organisations like Genomics England, research organisations, healthcare organisations, we often have missions and strategies that are about the benefit for society, that we do this work for the benefit of all, for the benefit of society. We want a world where everyone can benefit from genomic healthcare, for instance. These are really common kind of strategies, motivations, and intentions that organisations have, but they're so top level that actually what does that mean on a practical day-to-day? So my role really came about from Genomics England being really committed to the idea of equity and wanting to achieve it. But actually, in reality, how you make that happen in the different functions of an organisation can be really quite tricky. So how do we think about equity when we think about the science, when we think about the research, when we think about the data, when we think about recruitment, when we think about someone's experience of being part of research? There are equity questions in all of those places. Florence: Mm-hmm Sasha: Importantly, the thing that I want to achieve is to really appreciate the fact that everyone thinks that this is important, and give them some of the skills so they can think about what kind of dealing with inequity in their area kind of means. But also kind of importantly, what the role also means is, like, there's equity and also there's assurance. So one of the things that doesn't quite always get attached to sometimes these conversations about equity, is that actually you can measure those things. So you can measure patients' experience. You can measure whether there was a benefit. You can measure whether there was a change in clinical outcome. So again, kind of using that example of the people on the bike, we can change things to meet people's needs, but actually we need to then kind of measure the times at the end of the race to see whether actually we improved the times for people now that we've made those adjustments. So that's what the equity and the assurance means, right? So the equity is kind of putting things in the system or in the design that we want to have the impact of fairness, but the assurance is, and how am I monitoring and measuring that so that I can say, "Well, actually, that was a successful change. I would do that again, or I wouldn't do that again." Florence: Well, I think we'll finish there, but that was such an interesting conversation, Sasha, thank you so much for coming on and, and taking the time to talk to us. Sasha: No problem. Thank you. Florence: If you want to hear more Explain episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

In this episode of Behind the Genes, we explore how personalised cancer vaccines are being developed, and how genomics and AI could help make these treatments more precise. Our host, Florence Cornish is joined by: Dr Victoria Goss, Associate Professor of Early Diagnosis and Translational Research at Southampton Clinical Trials Unit and head of the Southampton Clinical Trials Unit Cancer Vaccine Launchpad team Professor Lennard Lee, Associate professor at the University of Oxford, Consultant Medical Oncologist, NHS Ali Richards, a participant who took part in a cancer vaccine clinical trial Together they discuss how cancer vaccines train the immune system to recognise cancer, how genomic information can help identify the unique features of an individual’s tumour, and how AI could help researchers analyse genomic data and accelerate the development of new cancer vaccines. “The reason I said yes was because my treatment really was punishing. It was so many side effects to it. The cancer never made me feel sick, but the treatment made me really sick. So I said yes because I just wanted to help other people not have to go through what I went through.” Transcript [00:00:00] Florence: What if a vaccine could help treat cancer? Hello and welcome to Behind the Genes, the podcast that brings you the stories, research, and innovations shaping the future of genomic healthcare. Today, we're going to be talking about cancer vaccines, how they're being developed with the help of AI, what role genomics has to play, and what it could mean for patients. [00:00:23] Florence: I'm Florence Cornish, and joining me today we have Dr Victoria Goss, who leads cancer vaccine research at Southampton Clinical Trials Unit; we have Professor Lennard Lee, who is a medical oncologist and Associate Professor at the University of Oxford; and Ali Richards, who took part in the Southampton Cancer Vaccine Programme. [00:00:45] Florence: I think before we get into cancer vaccines specifically, it might be good to start with the basics. So vaccines are something most of us have heard of and probably experienced as well, but we don't always necessarily understand how they work. So Lennard, can I come to you to explain what a vaccine actually is, how it works with our immune system, maybe at the most basic level for those who might not have a scientific background? [00:01:19] Lennard: Thanks, Florence. What's a vaccine? Very, very simply, something that protects your body from disease. We've had a few when we were younger, like which protects you against meningitis or hepatitis or different types of infections that can affect children. [00:01:36] Lennard: And it really does show that your immune system is really powerful. Every day, it looks around trying to work out what's there which shouldn't be there and takes care of it. And ideally, your immune system just works in the background without causing any problems. And so what a vaccine does is it really helps the body understand something that's abnormal. [00:01:55] Lennard: And the vision here is that you can use this technology to hopefully patrol against cancer, because half the people out there will never get cancer. They are the maybe the lucky ones or maybe the ones with a good immune response. And so a vaccine is basically giving your immune system a wanted poster: [00:02:11] Lennard: "This is what threat looks like. This is what you need to control". [00:02:16] Florence: And I think you mentioned some great examples there. There are lots of common examples of vaccines people might have heard of. I think maybe the flu vaccine is probably a common one that people are thinking about in the wintertime. I think another one is maybe the HPV vaccine. [00:02:29] Florence: Lennard, could you explain a bit more to our listeners about the HPV vaccine? What it is, how it works? I think people often think of it as a type of cancer vaccine, but actually it's targeting a virus. Is that right? [00:02:41] Lennard: Yeah, that's correct. So this is now a vaccine which has been rolled out across the NHS, and it's actually worked really well to get rid of a few cancer types, which is incredible. [00:02:51] Lennard: And why is that important? Well, cancer can be caused by many, many different things. Sometimes it's because you've done things like smoking or weight plays a role or just bad luck or the genes that you've inherited. But some cancer types are caused by viruses. And so many people nowadays are getting the HPV vaccine to stop cancer types like cervical cancer, hopefully head and neck cancer, and many of the rarer cancer types. [00:03:21] Lennard: And so again, what you're doing here is you're taking the immune response, telling it the body shouldn't get this virus and hopefully prevent some of the bad consequence of getting this viral infection, like cancers. [00:03:33] Florence: Thank you. That's really helpful to understand. So we've talked about how vaccines can be used to treat viruses, and I think most of us, when we hear the word ‘vaccine’, we probably do associate it with something that stops us from getting ill. [00:03:46] Florence: Victoria, could you tell us about how vaccines could be used to treat cancer? [00:03:50] Victoria: Yeah, absolutely, and it is great to be here today. Thank you. So Lennard's already sort of spoken about preventative vaccines, and when we think about cancer vaccines, we're thinking about therapeutic vaccines. So we're thinking about training the immune system to recognise the cancer as something that needs to be dealt with because cancer is really tricky because it's our own cells that have gone wrong, if you like. [00:04:16] Victoria: But that means it also is very good at evading those signals which tell the immune system that it needs to be cleared. So the analogy that Lennard has already given of a cancer vaccine sort of creating a wanted poster sort of builds on an analogy from one of your previous podcasts where they described the immune system as like the police almost trying to catch criminals, which are the cancer cells. [00:04:41] Victoria: And the cancer vaccine analogy builds on that. So you've created a wanted poster which is training and giving the police more information about what those cancer cells look like. And then when we think about building on that with sort of personalised cancer vaccines, which is an incredibly exciting step when we think about the development of how cancer vaccines can be used, sort of really individualised therapy going forward, that wanted poster gets even more specific. [00:05:07] Victoria: It's almost like giving a phone number or an address for that specific cancer type that is very specific to that patient. So the therapeutic vaccine is, is targeting the immune system. It's training our immune system to recognise the cancer as something that needs to be dealt with. [00:05:26] Florence: It's funny you mentioned that analogy because I was just about to point listeners to that episode. If anyone wants to learn more about cancer vaccines specifically, you can check out our previous Genomics 101 podcast episode called ‘What Are Cancer Vaccines?’ So Ali, I think I'd love to bring you in at this point because you have experienced this from the patient side of things. [00:05:49] Florence: Could you tell us a little bit about your journey, your cancer diagnosis and treatment, and maybe more about the clinical trial you were part of, if you feel comfortable sharing that? [00:05:57] Ali: Yeah, sure. Hi, Florence. It was Christmas 2015, and I felt a lump in my neck. And maybe because I'm a woman and we're always taught to treat lumps seriously, in the January I made an appointment with the GP, and she very quickly fast-tracked me through to the hospital. [00:06:19] Ali: And January 2016, I got a diagnosis. It was a tumour on the base of my tongue at the left, and I was told it was caused by a variation of the HPV virus. So yeah, that was all a bit of a shock. I was shocked and I was scared, but I was also really angry because I look after myself. I eat well, all those things. [00:06:45] Ali: It's just bad luck that it was a virus that my body couldn't deal with. I just, I felt guilty as well because of what I was gonna put the family through. So I had various scans and tests. I had an operation to remove my tonsils, although we soon discovered there weren't any left anyway. And they took a biopsy, which I didn't know at the time, but turned out to be important later on for the trial. [00:07:15] Ali: Then I had to have a whole load of prep beforehand because of the impact of the treatment. So I had to have restorative dentistry, audiology tests. I had a PEG fitted, that's a feeding tube, in my stomach, and I thought, "Surely it's not going to be this bad." But that PEG, that feeding tube was a blessing in the end. [00:07:40] Ali: And I had a mask made, and the mask fits you and basically pins you down to the radiotherapy table so you don't move when... because it's very precisely targeted at your tumour. So yeah, I went on to have five sessions of chemo, which felt quite easy. The radiotherapy was the really, really tough part. I had, uh, seven weeks of it, 35 sessions. [00:08:08] Ali: So that was, yeah, that was a challenge. [00:08:11] Florence: Thank you, Ali. Thank you for sharing that. I think it's always really valuable to get that patient perspective when we're talking about things like this. Lennard, I wanted to come back to you now to talk about the different types of vaccines that exist and which ones are being used specifically in the treatment of cancer. [00:08:30] Lennard: Um, thanks, Florence. And Ali, are you 10 years now down the line since your diagnosis? [00:08:34] Ali: Yeah, it feels good. [00:08:37] Lennard: Congratulations. [00:08:38] Ali: Yeah, yeah. It feels good. I really valued the follow-up checks that I had, both from my oncologist, but also I got some through the trial, and it really helped restore some confidence in myself and my body to deal with things and to be able to move on as well. [00:08:56] Lennard: Oh, well done. That's fantastic because you telling us that story just really brings it to life about how scary this can be and also the fact that you had to go through all those sessions, thirty-five sessions and, um, and now you're 10 years down the line and still talking and giving hope- [00:09:11] Ali: Yeah ... [00:09:11] Lennard: that new technology still comes, so thanks, Ali. [00:09:13] Ali: That's a pleasure. [00:09:14] Lennard: Um, yeah, so Frances, this is what's really exciting. What types of vaccines are there? Well, first thing to say is that we're really good in this country about vaccine research. If you look around the world, what are we good at? Well, everyone knows that we developed the pandemic vaccine, and actually that technology is something that we can control. [00:09:31] Lennard: We're world leaders at. It's quite cheap technology, and it's something that we are really good at bringing to patients. And Ali's our testament where she got on the trial, she helped test it and really pioneered new ways of research. So what types of vaccines are there? Well, I think we talked to the first bit where Victoria taught us that some of them can treat cancers and some of them can maybe prevent cancers. [00:09:53] Lennard: And the HPV's one which is maybe be able to do both one day, which is brilliant. What would like... what else do people know about? Well, people might know that there are different types of technologies. So if we think back a few years now, back to 2020, there are some which are viral-based, and some which are mRNA based. [00:10:12] Lennard: Both of these were new technologies which the whole population of the world came together to create and some of them are peptide-based. So there's probably three different types here. The protein ones or peptide one, which you always had, and then in the last five years, it's an incredible time to be alive, where new vaccine technology comes through, it's more effective and safer. [00:10:32] Lennard: These are the viral ones and mRNA ones, and everyone's now pursuing all of these to try and make sure that we can maybe treat cancer in future. [00:10:41] Florence: Can I possibly pick your brain a little bit more about the mRNA ones specifically? I think as you mentioned, lots of people might have heard of those during COVID. [00:10:50] Florence: Could you maybe explain a little bit more about those and how they work? [00:10:53] Lennard: Yeah. So this is going to take us all the way back to GCE biology now. If you remember - and we are Genomics England, so we, we got to work out why genomics is important, and we'll probably get to this. But remember, genes make RNA, which then makes protein. [00:11:11] Lennard: And so if you're trying to reprogramme the immune response, you could give your body a protein, the back end of it. You can maybe give it an RNA, which is a blueprint too. And so what an mRNA vaccine is, it's a way of giving the blueprint or the instructions to the body of what to recognise, what the cancer looks like, um, um, or what the virus looks like, and target it. [00:11:32] Lennard: If you want the analogy, well, for those people who had the pandemic vaccines, the ones which was mRNA based was, uh, the Pfizer one, and that worked really, really well. Cheap to make, easy to produce, and, uh, it's just a jab. And so people are now exploring that for cancer treatment now. Take new technology, which has only been developed five years ago, technology, which is just a blueprint, cheap to make, easy to update, and now we're targeting cancer. [00:11:59] Lennard: Um, so that's basically what an mRNA vaccine is, giving the body the blueprint or the instruction of what a cancer looks like and trying to target that cancer. [00:12:08] Florence: And you kind of alluded to it a little bit in your answer, but, um, it would be good to know more about where genomics comes into all of this. You know, why is it such an important part of developing vaccines? [00:12:18] Lennard: And that's a great question, and really comes back to our second strengths, which is that we're really good at vaccine research, and yet we are also world leaders at genomic research. It's a really exciting time because, um, when Victoria and me and Ally at school, we would-- we, we learnt about that race to sequence the first human genome. [00:12:38] Lennard: It was really exciting because for the first time, we can see every single genetic base in every human, and that used to cost billions of pounds to do that, and it would take many months or years to do that Fast-forward a few years, and then now Genomics England delivered the next success for humanity. [00:12:57] Lennard: I think it was about 2015 to 2017 where they, they did 100,000 Genome Project, where the UK led the world in sequencing 100,000 people, including people with cancer, to try and understand what caused their cancer, what the risk factors are. And why is that relevant now? Well, it's because if you know what a cancer looks like, then you know what the abnormality is, well, then you can vaccinate against it. [00:13:22] Lennard: So we've now gone from this amazing arc of discovery here, where when we were at school, we worked out what the human genome looks like. We can sequence it end to end and see in all its detail. Then a, an amazing organisation came out the ground called Genomic England, which shows that you can run it in the NHS. [00:13:39] Lennard: 100,000 people could do it. And now we're making the next big jump now, which is it's not just going to give you a diagnosis, but maybe becomes a drug and a vaccine in future. And actually, probably it already has because Ali's that example, a success example of it happening. [00:13:54] Florence: Yeah, I wanted to actually ask you about that, Ali. [00:13:56] Florence: So just as you were saying, Lennard, it kind of... The cancer vaccine sounds quite futuristic, but as you said, it's, it's sort of already happening. So Ali, do you remember kind of how you first heard about the cancer vaccine trial? [00:14:11] Ali: Yeah. I had a bit of an unfortunate time because after all that radio and chemo, my cancer still hadn't gone, and I had to have an operation to remove lymph nodes. [00:14:22] Ali: But my oncologist at Poole Hospital, who's a fantastic woman, she had been involved, unknown to me, in the some of the thinking behind the trial, and particularly that she could recruit people because they were sat in her office. So she asked me if I'd like to take part, and without knowing anything, I said yes. [00:14:49] Ali: And the reason I said yes was because my treatment really was punishing. It was so many side effects to it. The cancer never made me feel sick, but the treatment made me really sick. So I said yes because I just wanted to help other people not have to go through what I went through. I didn't really understand it, if I'm perfectly honest. [00:15:16] Ali: I didn't really know what was going on, but then I'm not, you know, a super brain like Lennard and Victoria. I knew that I just wanted to do something to help people going forward, not having to deal with the same. So yeah, I put my hand up and there I was on the trial. [00:15:37] Florence: So you mentioned there the, the really horrible side effects that you got from your original treatment. Did you have, um, what was your experience with side effects with the vaccine? Was it similar? Was it different? [00:15:47] Ali: Oh, no, the, the vaccine was like a holiday compared to the treatment. Absolutely. At, at worst, in the first few treatments, you felt a bit like you had a cold, bad cold coming on, maybe slightly flu-y, but you took, you were given Ibuprofen at the same time as you had the vaccine. [00:16:10] Ali: So no, it, the treatment with the vaccine was an absolute breeze. Which is kind of like, yes, this is what I want for people. You know, not, not the radiotherapy, not the chemo. So yeah, it was, it was really very easy by comparison. [00:16:29] Florence: Oh, I'm so glad to hear that that was your experience. I'm just curious now also, was there anything that surprised you about the trial? [00:16:35] Florence: You said there that you didn't really, like, have an understanding of cancer vaccines. You, you agreed to it straight away. Was there anything that maybe, like, you weren't expecting or surprised you? [00:16:45] Ali: I think it surprised me that it was really quite easy. [00:16:48] Florence: Yeah. [00:16:49] Ali: Uh, I was delighted to have the team I had looking after me because they were fantastic. It all felt very simple. [00:16:59] Ali: And how nice that was. You know, if I could've had that instead of all my previous treatments, um, it would've, it would've made everyone's life so much easier. And I guess, I don't know about the cost of drugs, but I guess the cost to the NHS would've been less because I wasn't in and out of hospital, I wasn't having to have all these extra things done, and all this extra support like dieticians and so on because I had to have my feed tube replaced. [00:17:35] Ali: So all of that is impacts on the NHS, whereas this was very simple. [00:17:40] Florence: I wanted to come to you now, Victoria, and ask you about the outcomes of this trial that Ali took part in or other trials like it, and whether we know yet what the broader implications of, of these advances might be. [00:17:55] Victoria: So I think what we need to think about when we're thinking about developing these treatments and sort of evaluating the treatments at each stage is that it goes through a very clear pathway of progression, and Ali was involved in one of the, the earliest stages of that progression. [00:18:09] Victoria: And it's, it's always amazing to me to hear your story, Ali, and to know that patients are willing to take part in the research and that's what allows us to develo

In this explainer episode, we’ve asked Dr Antonio D'Alessio, Medical Oncologist at Guys and St Thomas Foundation Trust, to explain cancer vaccines and how they work. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk . You can download the transcript or read it below. Florence: What are cancer vaccines and how do they work? My name is Florence Cornish, and today I'm joined by Antonio D’Alessio, who is a medical oncologist ay Guy's and St Thomas' Foundation Trust and King's College. And he's going to be telling us much more about the topic. So Antonio, before we get into cancer vaccines, I wanted to first ask you about cancer. I know it's a pretty broad term, and it refers to the uncontrolled growth of cells in the body, but maybe it would be helpful for you to explain a little bit more about what cancer actually is, like what that term means, especially for listeners out there who might not have that scientific background. Antonio: Yeah, of course. And first of all, thanks for inviting me today. Well, that's a big question. The point is that we know that in our bodies there are billions of cells, and all of these cells, they divide, they do their job, and they know when to die on schedule. The point is that sometimes there are cells that ignore this instruction and just keep reproducing and growing, and this is when cancer grows. Our bodies have systems, which is the immune system, to recognize when this happens so that the immune system can recognize the cancer cells that are growing too much. They attack them and destroy them. But unfortunately, sometimes cancer is quite clever, they manage to escape from the immune system and starts growing without control, and that's when cancer starts. Florence: And so, what are the standard treatments that we use for cancer at the moment? Antonio: Well, broadly speaking, I would say that we have three types of cancer treatments. One, it's surgery, where we just cut the cancer out. Then we have radiotherapy, where we basically induce targeted damage to the cancer. And then we have a very broad umbrella term that is systemic therapy. Systemic therapies can be chemotherapy, can be targeted therapies, and that can be immunotherapy. In particular, immunotherapy is quite exciting because over the past 20 years, we have learned how to boost the immune system of patients, so that's the white blood cells, the immune system of patients that can recognize cancer cells and attack them. Sort of imagine that cancers hide behind an invisibility cloak, and immunotherapy helps unveil the cancer so that the immune system can recognize the cancer again and attack it. And vaccines and cancer vaccines are part of this family of immunotherapy drugs. Florence: Yeah so speaking about that, I think lots of listeners might have heard of the term cancer vaccine before, obviously, its the topic of this episode. And I think the term cancer vaccine sounds very interesting and promising, but also maybe a little bit intimidating as well. So maybe you could tell me more about what a cancer vaccine is kind of at the most basic level. Antonio: Well, cancer vaccine is a vaccine, and we have received so many vaccines in our lives that our body basically has learnt already how to process a vaccine. Imagine a vaccine as a wanted poster. So, we give the body the instructions to recognise something that shouldn't be there, and the immune system knows how to do it. So, the job of the immune system is to recognize strangers in our bodies - that can be microbes, bacteria, viruses, and also cancers. And sometimes with a vaccine, we sort of help the immune system to do its job a bit better. And with vaccines, we provide the instructions to recognize these strangers in our body and help the immune system to, to get rid of them. And in particular, for cancer vaccines, we have different types of cancer vaccines. There's a family of cancer vaccines that are called preventative, where we can try to give a vaccine even before the cancer develops to reduce the risk that the cancer develops. And, this is more early in the development. While we have, another family of cancer vaccine, which are mostly mRNA cancer vaccines that are called therapeutic. So these are cancer vaccines that are given to patients who already have cancer, maybe who had the surgery for their cancers, so that the aim of the cancer vaccine is to boost immune system and reduce the chances that the cancer comes back after surgery, or, help other types of immunotherapy work better together with vaccine against the cancer. Florence: So, I think for me at Genomics England, the mRNA cancer vaccines are probably most relevant to the work that we do here as an organization. Could you explain a little bit more about how those ones work specifically? Antonio: Yeah, that's an exciting field, right? The mRNA vaccine. So, let's split this into different words, mRNA and vaccine. We have just covered what vaccine means. We just have to think mRNA as just instructions. So we give the body of the patients the instruction to recognize the cancer. And the mRNA is basically the instruction for the immune system to recognize some of the proteins that are expressed on the cancer cells, so that's the white blood cells, the own white blood cells of the patients that can be more alert and identify the cancer cells if they are around. And in particular, imagine when we give the mRNA vaccine, it's like we are giving the picture of a suspect to the police, right? The police is the immune system of the patients, and the suspect is the cancer. And so, the immune system, so the police of our body, can go around the body, can go around the bloodstream, can go around the organs, and if they see the suspect, they are, they are already alerted, and they can tackle it, attack it, and destroy it before it develops into, into a cancer that can be seen on the scans. Florence: And are these types or other types of cancer vaccines being used in the clinic at all in real medical settings already? Antonio: Well, I wouldn't say that we are using that in clinical practice, but probably in the future we will, and we are working hard to make sure that we will be able to use cancer vaccine for our patients. At this stage, we are using cancer vaccines as part of clinical trials, and these clinical trials cover different types of cancer types, different types of setting, together with other drugs or given alone after surgery, for instance. And the NHS England, Genomics England and NIHR, they launched this massive infrastructure that is called the Cancer Vaccine Launchpad. And it is aimed specifically to match the NHS cancer patients with personalized mRNA vaccine trials, so that once we have the results of those trials and we are ready to deploy it in clinical practice, then we already have the infrastructure to do that promptly, hopefully in the next future. Florence: Mm-hmm. Yeah, so do you see a future where cancer vaccines are used in routine care? Antonio: Well, we are working towards that. And I, and I do see a future where we're going to use that. I don't know when. Probably it will take still a few years. But the, for example, in the UK and in England in particular, we have a national cancer plan, and the national cancer plan for this year has identified cancer vaccine as a top priority for our health system. And this is because this is a technology that can be scalable, that can be widely deployed once it's demonstrated to be working. And at this stage, there are still some open questions, like which cancer types in which setting, which patients would benefit from it. But once we address these open questions in clinical trials, then I do believe that we'll be able to use that in the, in the future. Florence: I think we'll finish there. Thank you so much, Antonio, for coming on and for taking the time to talk to us. Antonio: Thank you Florence, and thank you for the invite. Florence: If listeners want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

Two years after researchers identified ReNU syndrome, where are we now? In 2024, two independent research teams identified the genetic cause of ReNU syndrome, a rare neurodevelopmental condition affecting thousands of people worldwide. The discovery marked the beginning of a new chapter for families searching for answers and opened up exciting new avenues for research. In this episode, host Sharon Jones revisits the story to explore what has happened since that breakthrough. She is joined by: Professor Nicky Whiffin, Associate Professor and Wellcome Career Development Fellow at Big Data Institute and Centre for Human Genetics, University of Oxford Christina Cox, Co-founder of ReNU Syndrome UK and parent of a child with ReNU syndrome Dr Ana Lisa Tavares, Clinical Lead for Rare Disease at Genomics England Together, they discuss how researchers around the world have built on the original discovery to deepen our understanding of ReNU syndrome, why studying the non-coding regions of our DNA is revealing previously unknown rare conditions, and how collaboration between researchers, clinicians and families is accelerating progress. They also explore how the growing ReNU community is supporting newly diagnosed families and what the future could hold for new treatments. Links: Previous episode detailing the discovery of ReNU Syndrome ReNU Syndrome UK's website Original research paper from Nicky's team in Oxford Original research paper from the team based in New York “It's been only two years since our paper came out about this, and in that time, there are now patient family groups that have been set up all around the world. There is the one in the UK led by Christina and the others. There's the one in the US that's led by a group of four women, and there are ones in France, Spain, like, literally all around the world. And all of these groups are also somewhat coordinated. The leads of these groups meet with each other. They've organised meetups. I've been to ones in the US, the UK, and in France. So the fact that they can mobilise all of that and create such a community so quickly is absolutely incredible.” You can download the transcript , or read it below. [00:00:00] Sharon: In 2024, two independent research teams identified a genetic cause of a rare neurodevelopmental condition affecting thousands of people around the world. Since then, that initial groundbreaking discovery has grown into something much bigger, bringing together families, researchers, and clinicians, and building a clearer picture of what we now know as ReNU syndrome. [00:00:26] Sharon: Welcome to Behind the Genes, the podcast that covers everything from cutting-edge research to real-life stories in genomic healthcare. I'm Sharon Jones, and in today's episode, we're looking at what's happened since that discovery, what researchers are continuing to learn, and what the future could hold for people living with ReNU Syndrome and their families. [00:00:46] Sharon: To help us understand more, I'm joined by Professor Nicky Whiffin, Christina Cox, and Dr. Ana Lisa Tavares. So, two papers were published around the same time for this condition. To start us off, Nicky, you worked on one of these papers. Could you explain how this journey first began? [00:01:05] Nicky: Yeah, so this was two years ago now, back in early 2024, where two research teams, so us based in Oxford and a, a group based in New York, were both looking at the data within the National Genomics Research Library, and we both kind of somewhat simultaneously found that there was variance in this very, very small gene, it's called RNU4-2, were found in individuals with previously undiagnosed neurodevelopmental disorders. [00:01:39] Nicky: And this was very, very striking because we initially actually identified the same single DNA change or mutation in 40 or so different individuals within the National Genomics Research Library, and we normally expect to see a whole host of different variants. We don't expect to see the same one. [00:01:59] Nicky: So this was a really, really surprising finding. And it was through a collaboration, large scale collaboration across the world where we started contacting our other collaborators who have similar collections of patients who have been genome sequenced to ask if they had any individuals with DNA changes in this gene. [00:02:17] Nicky: And we found some in the US, some in, in Australia, some in France and Germany. So very, very quickly built up this, this complete picture of variants in this gene, causing this rare neurodevelopmental disorder [00:02:35] Sharon: of people finding it at the same time, what, what did that feel like? [00:02:39] Sharon: Like, give us a ense of, like, that compelling, "We think we found something." What was that like? [00:02:46] Nicky: I didn't believe it initially. You're always told when you're a scientist that if it looks too good to be true, it's, it's not true, and this basically lit up like a beacon. There's this particularly one DNA change that we found in, um, I think it was about 40 different individuals, and we don't really expect that to be the case. [00:03:04] Nicky: We normally expect these genetic variants to be somewhat randomly distributed across the genome. So to find 40 individuals with exactly the same DNA change was very, very surprising. So initially, I didn't believe it. The whole team, including folks at Genomics England, spent a lot of time trying to check that these variants were real and tried to disprove the result, tried to find any other way in which any other reason why we would be seeing this. [00:03:31] Nicky: And after a little while, we had to concede that we couldn't disprove it, so it must be true, and that, that was a very exciting moment. [00:03:38] Sharon Jones: Was it the case that over in the States, the exact same thing was happening? [00:03:42] Nicky: I think we found out when we were both speaking at the same conference, actually. So we didn't actually know that we, that we'd both come across the same result. [00:03:49] Sharon: If you want to check out our previous episode on this initial discovery, you'll find a link to it in the episode description. [00:04:00] Sharon: So Christina, tell us a bit about your situation, your family situation, and for our listeners, what ReNU is. [00:04:05] Christina: So ReNU is, to us, is a family. We got a family when we got diagnosed with ReNU. Beau - Arabella - already had other diagnosises, but people had always said to us, "Oh, there's something else. There's something else. [00:04:20] Christina: We're not sure what it is, but there will be something." And then when we got ReNU, it was like, "Oh, okay, amazing. What do we do? What is it?" Because there was only four lines on Wikipedia when we first got told about it, and there wasn't anything that, ourselves could find. So we kind of went onto Facebook and looked for groups and different people, and there wasn't really anything except for Jess in America. [00:04:46] Christina: And then it grew, and then it kind of, we ended up finding more people in the UK and, like, all over. But for us, it didn't really change how we perceived Beau. It just made life easier. Like, knowing there was other families out there that we could find advice from and support from, and that we kind of knew what we had and going forward then, like, finding researchers and connecting with everybody. [00:05:15] Sharon: Yeah. And for those who don't know, can you talk about what ReNU is? Like, how does it affect Beau? [00:05:20] Christina: So with Beau and ReNU , it affects her with developmental delay. She's non-verbal. She's incontinent. She suffers for walking, so she can do a little bit of walking, but she needs a wheelchair It affects her mood swings. [00:05:38] Christina: It just affects everything. Although she has it, she's still a happy, outgoing, very stubborn, just kind of "keep-going" child. But it affects her in everything, like eating, sleeping. [00:05:51] Sharon: It sounds like life is, you know, very challenging on a day-to-day basis, lots of considerations. How did you feel when you finally got this diagnosis after years of wondering and waiting, not knowing? [00:06:02] Christina: Finding out was, like, really emotional because it was like, "Oh, wow, so we have this diagnosis. Now what? What are we looking for? What's going to happen?" And then we were kind of like, "Oh, but there's not many people that had it." Because we found out in the August, so then it was trying to find people. But it has been life-changing to know that we're not on our own and that there is other people around. [00:06:28] Sharon: Yeah, tell us a bit more about that. How did it feel to get that diagnosis? [00:06:32] Christina: It was quite strange because our pediatrician rang us and said, "Oh, we've got a diagnosis. She's got RNU4-2." And we were like, "Okay, so what's that?" And she's like, "I don't really know. There's four lines on Wikipedia at the moment." [00:06:46] Christina: She goes, "I don't like Wikipedia," but we still kind of... That was it. So then we went on a mission to find and look for where we could find support and find other families. [00:06:58] Christina: At that point, I didn't know of anybody in the UK, and my husband found Jessica in America. What then, kind of, we had somebody to talk to, and then families in the UK kind of started appearing. [00:07:09] Christina: So we ended up getting a whole network of people to bounce ideas off and talk about how it affects their children and what's for the future and things like that. It was really nice. [00:07:22] Sharon: Yeah, yeah, I can imagine. So Ana Lisa, how do these findings contribute to a growing understanding of the condition? [00:07:29] Ana Lisa: So this was an amazing discovery. Although we're finding new rare conditions quite often, not on this sort of scale. It was also an amazing finding because a lot of the genes that we know are associated with rare conditions are genes that encode proteins, and in the 100,000 Genomes Project, we were doing whole genome sequencing, and Nicky and her team were looking in the parts of the genome that don't encode for proteins. [00:08:03] Ana Lisa: And so this was, uh, exciting from that point of view as well. So the vast majority of our genome, more than 98%, does not encode for proteins, but it's relatively unexplored. And if we think about our genome and the letter code that makes it up, which is the manual for how our bodies are built, and grow and function day-to-day. [00:08:30] Ana Lisa: Those 3 billion letters, if you, if you printed them out in a 12 font regular print, it would stretch so far you could fly, I think, from London to Paris several times, maybe three times or something. And so, this actual gene is a very, very small gene, less than 150 of those letters. So again, it was incredible to find that by comparing across many, many different genomes in the National Genomic Research Library. [00:09:00] Ana Lisa: Going back to your question about a growing understanding of a condition, it was a completely new condition, but it also opened up looking at other related genes and actually now more disorders that are being found, like RNU2-2 by colleagues in the US, and that might be one of the most common recessive genetic neurodevelopmental disorders. [00:09:27] Ana Lisa: So it's really, really opened up this understanding about these types of disorders and also those non-coding parts of our genome and the power of collaboration and being able to look across many different whole genomes at the same time. [00:09:44] Sharon: Yeah. And Nicky, you've been involved in much of this research journey. [00:09:50] Sharon: What have been some of the biggest advances or learnings for you so far? [00:09:55] Nicky: I think the biggest one is just how common, or how frequent, these disorders are. So what we discovered recently in terms of new genetic disorders were rarer and rarer conditions, and that's why we hadn't seen them before. But from going from looking at the protein coding genes to looking at these non-coding genes, we found something that was as frequent as disorders that were found in the early 2010s when we first had large-scale sequencing projects that looked at the protein coding genes. [00:10:26] Nicky: So that was really, really surprising. And we now know there's this whole class of disorders. So RN4-2, this gene encodes this -- Well, it produces this small RNA that works in this huge molecular machine that is called the Splicer Zone, that mediates the processing of most of the other genes across the genome. [00:10:50] Nicky: And there are lots of these little RNAs that work in this molecular machine that are called the small nuclear RNAs or the snRNAs And we now know that there are a whole multitude of different disorders associated with different ones of these spliceosomal small nuclear RNAs, and that's really incredible. [00:11:09] Nicky: And for RNU4-2 itself, we also now know that there are, there's not just RENE syndrome, uh, which is a dominant disorder caused by chance de novo variants that are newly arisen in a child, but also a recessive disorder where a child inherits one, uh, gene mutation from each parent. And also another finding that there is a region of the gene where we find DNA changes that cause retinitis pigmentosa, so a retinal phenotype. So we now know a huge amount more about this single gene, but also all of this different class of genes or RNAs that work in the same molecular machine, uh, which is, is really fascinating biologically [00:11:52] Ana Lisa: Vicky, while you were talking, I was thinking about the splicing and how a bit like this podcast recording, you're going to splice out the kind of extreme, the noise that wasn't supposed to be there. [00:12:03] Ana Lisa: And actually, you could make slightly different versions of this podcast, couldn't you? And that's, that's what, what's happening in our bodies for a lot of our genes that, that the kind of output can be varied slightly. [00:12:15] Sharon: So Christina, how has collaboration been involved across the community and with researchers? [00:12:21] Sharon: You know, what sort of things have you been doing? [00:12:23] Christina Cox: So it's amazing to have researchers that are so open and amazing to work with the families. So at the moment, we are just putting together like a panel to discuss questions from families, to then be able to answer families, to work very closely with the researchers for what things are happening and the progress within. [00:12:47] Christina: It's just amazing to be able to work with researchers. They're just fantastic. [00:12:52] Sharon: And from what I understand, like, you, you have a charity, don't you? Can you tell us a bit more about that and how that came about? [00:12:58] Christina: So we have ReNU Syndrome UK, and it came about as there was a group of us parents that were like, we wanted to be able to support other families, knowing what it was like for us when we first started. [00:13:12] Christina: It was very difficult. So we wanted to start a charity that can support families and signpost them, give them the opportunity to have family meetups once or twice a year, so we can work with scientists and specialists to keep everybody in the community, like the ReNU family, up to date. But being able to connect with so many families, because a lot of the doctors don't really know of ReNU Syndrome yet. [00:13:46] Christina: So if we have a problem or a question, we put it in the WhatsApp group, and then somebody can answer it because they've been through it, or they, they've just asked the question. So it's just an amazing resource for everybody [00:14:02] Sharon Jones: That sounds amazing, and it sounds like you've all obviously become experts by experience. [00:14:04] Sharon: So, like you say, you kind of know more, you know, as the science develops, but you're living it every single day [00:14:10] Christina: It's kind of, you go into the hospital and they're like, "Oh, what's ReNU Syndrome?" And then you're like, "Ugh." So, then you just have to say it all. But, and then it's kind of them bringing, teaching new people who don't know about it in the medical professional. [00:14:26] Christina: We always give them the website so that they can go and then find, but being able to put more medical stuff on the website, it just helps everybody, and it's just broadening it out to as many people as possible. Because there's still a lot of people undiagnosed with RNU syndrome. It's, now it's easier to be signposted, but it's just keeping that connection. [00:14:49] Sharon: Yeah. And, and from what I understand, it's got quite an interesting sort of origin of a name, RNU. Where did that... Do you know much more about where that came from? [00:14:57] Christina: So, Nicky is the amazing person who, um, sorted the name and um, the origin. So, I'll pass that over to Nicky to answer that question because she's just amazing [00:15:11] Nicky: Uh, so the name ReNU syndrome is an interesting story. [00:15:13] Nicky: So, a lot of disorders or diseases are named after people. So, we all know Alzheimer's, Parkinson's, etc. And they're often scientists or clinicians that have spent a lot of time working on them. I think that's a little bit odd. I don't think it's the first thing that somebody should know about a disorder, is the name of somebody who's, who's worked on it or studied it. [00:15:36] Nicky: But they're a very, it's very hard to find an alternative. When we were initially doing the press release around our paper, we had a quote from one of the mothers, Nicole Cedar, who has a, a wonderful daughter called Mia Joy, and she said that within their family, they like to refer to RNU, to RNU4-2 as ReNU, which is a really nice play on the RNU in the gene name. [00:16:00] Nicky: So then I had an idea, okay, let's just change the spelling to make the, the kind of big R, little E, large N-U, then it would link to the gene name, but also would be a name that speaks to hope and the renewed hope of being given a diagnosis. [00:16:13] Sharon: Yeah, absolutely, and that's a great, a great story and a great way of kind of making it feel like there is, there is always hope. [00:16:20] Sharon: So, you know, Nicky, you're now part of the patient community. In a way. You know, so how does it feel to be on that other side of it from that sort of research perspective and now kind of, you know, in that, in that community? [00:16:34] Nicky: It's amazing. I've got a new family as well. It's not, not just Christina and everybody. [00:16:39] Nicky: I kind of, I'm a, a basic scientist. I'm not a clinician. Up until this point, we've always been one or two steps removed from actually interacting with the families themselves. Um, so my life has changed an awful lot over the last couple of years, uh, where now, um, I kind of talk to Christina or the folks in the US, really regularly, kind of on a weekly basis. [00:17:02] Nicky: Um, so that's really different. And I just kind of want to highlight just what these families have achieved. So it's been only two years since our paper came out about this, and in that time, there are now patient family groups that have been set up all around the world. There is the one in the UK led by Christina and and the others. [00:17:26] Nicky: Um, there's the one in the US that's led by a group of four women, and there are ones in France, Spain, like, literally all around the world. And all of these groups are also somewhat coordinated. The leads of these groups meet with each other. They've organised meetups. I've been to ones in the US, the UK, and in France. [00:17:46] Nicky: So the fact that they can mobilise all of that and create such a community so quickly is absolutely incredible. And they've got families, they've got so many researchers that are interested in the cause. They're interacting with the p

In this explainer episode, we’ve asked Ella Davyson, Genomics Data Scientist, to explain the meaning of the term genomics. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk . You can download the transcript or read it below. [00:00:00] Florence: What is genomics? My name is Florence Cornish, and today I'm joined by Ella Davyson, who is a genomics data scientist here at Genomics England, and she is here to explain the topic in much more detail So, Ella, we obviously both work at Genomics England. This podcast is called Genomics 101, so I guess it's fitting that we have an episode dedicated to explaining the term 'genomics'. [00:00:26] But before we get into that, I think it would be good if you could first explain what we mean by the term 'genome'. [00:00:32] Ella: Thanks, Florence. The genome is, essentially you can think of it like a manual booklet, or instructions that the body uses in how to grow, survive, and function, and this is a manual that's in every single cell within our body, and it tells our cells exactly how to divide, how to survive. [00:00:54] For example, the genome in the pancreas, in pancreatic cells will tell those cells how to produce proteins such as insulin that we need to control our blood sugar. And also, the genome within our eye cells will tell the cells how to generate photoreceptors to enable us to see. So the genome is essentially like the ultimate guide that our body uses to tell it how to create everything that we need to survive going forwards. [00:01:25] Florence: So then, what do we mean by the term 'genomics'? [00:01:30] Ella: So, genomics is essentially the study of the entire human genome. So we study its structure and also how it functions, in terms of how is this instruction manual being read by the body, and how does that result in healthy human beings that we see today. [00:01:48] Florence: So when we're talking about studying DNA, lots of our listeners might have heard the term 'genetics', which kind of also refers to the study of DNA and genes, so it might be a little bit confusing. [00:01:58] So what's the difference between the two? What's the difference between genetics and genomics? [00:02:04] Ella: So genetics is specifically the study of genes in the genome, and genes are part of the instruction manual, that specifically tell the body to produce a certain thing. So, in our insulin example, there is an INS gene, so, which is the gene in the genome or the instruction manual that specifically tells the cells to make insulin and to produce this product. [00:02:30] There are many different genes in our genome, and genetics is the study of all of these. In contrast, genomics is the study of the entire instruction manual altogether, so that includes all of the genes in genetics and also everything else in the manual. So, genetics is limited to the study of these parts of the manual that clearly encode certain proteins or products such as insulin. Genomics is the study of everything all at once, everything under the bathroom sink. So yeah, the confusion I think can arise a lot because historically when we first started looking at DNA and researching genetics, we didn't have the technology to look at the whole genome all at once, and with older sequencing technologies we would focus on particular genes that we knew important for certain diseases. [00:03:19] So in diabetes, for example, they would instead specifically look at the insulin gene and see how does this influence diabetes, rather than looking at the entire instruction manual at once. Nowadays, we do have that technology, and that is what we do here at Genomics England, just use that to look at the entire genome rather than specific subsets of the genome, so specific genes. [00:03:45] We can look at everything in its entirety. So, you can kind of think of genomics as a much broader, more complete study of genetics. [00:03:56] Florence: So speaking of genomic testing, I don't know if you saw, but in the government's 10-year Health Plan that they published last year, they predicted that genomics could play a role in up to 50% of healthcare interactions. [00:04:08] Could you tell me a bit about why genomics is important in healthcare? [00:04:12] Ella: So that's a really exciting point, and I think one that we should be all striving towards. So, genomics can play a role in healthcare in so many different ways. I think before going into each of them, it's kind of maybe important just to illustrate that our genomes between two, two people are 99.9% the same. [00:04:38] So we're both humans. We are both the same species. There is 0.1% difference between two people's genomes, and those differences underlie all the uniqueness that makes a person a unique individual. [00:04:54] So personality, appearance and also risk to different health and disease outcomes. So that is where the role of genomics can come in, is to understand how the differences between people and their genetic makeup can influence maybe their risk for being more predisposed to developing a condition. Conditions such as Cystic Fibrosis or Huntington's disease that are specifically caused by genetic variants or mutations in genes that directly cause the condition. So it's a bit more maybe obvious, if you like, about how studying genetics in those, in those conditions can directly inform on how they arise, potential ways that we can better treat them. [00:05:52] So another way that genomics can be used in healthcare is through screening. So this is being piloted at the moment in the Generation Study by Genomics England which is applying whole genome sequencing to newborn babies to look for a range of conditions which are caused by genetic changes, all of which are treatable. [00:06:13] But importantly, screening will enable clinicians and families to know about these conditions much earlier and start life-changing treatment much, much sooner. So this is kind of already beginning to be, I think it will be showcased with this study in the next couple of years and the power of this in healthcare, I think can't really be overestimated. [00:06:40] Florence: And finally, just to finish off, is there anything coming up in the field of genomics that you're especially excited about? [00:06:48] Ella: There are loads of different things that I'm excited about in the field of genomics. I think probably maybe one that's most kind of relevant to clinical care is the possibility of doing more personalised medicine with treatments. [00:07:05] Often, at the moment, we majority have kind of one treatment for all when treating certain conditions, and sometimes these treatments aren't tolerated well by some people, and also some of these treatments just don't work well in some people as well. Sometimes there's a clear reason for these things, but more often than not, it's not entirely clear why some people might benefit more for some treatments or some people don't respond or don't react well to some treatments as well. [00:07:35] And understanding more, so there's a whole field about how genomics interacts with drugs and medicines, which is called pharmacogenomics, and its aim is to understand which medicine might be most effective or well-tolerated in certain people based on their genetics. And I think that will be kind of life-changing as well for some people, who are suffering from diseases where the medication is either not effective enough or is also affecting their quality of life. [00:08:10] Florence: Mm-hmm. [00:08:10] Ella: Because that is a whole other part of it as well is that sometimes these treatments for certain conditions are really hard to tolerate. [00:08:19] Other things that I'm excited about are just the technologies that are coming out at the moment mean that we can measure and understand a whole lot more about genomics than we used to be. So now we can say this gene is influencing this disease, but sometimes, you know, it's more complicated, and we now have the technology to measure all sorts of different things, so how our environment can influence our genes and how our genes react with each other. [00:08:57] So we're just getting, we're getting able to look at more and more, and I think we'll expand our understanding in a lot of conditions that unfortunately aren't very simple. [00:09:12] Florence: Well, I think we'll finish there. Thank you so much, Ella, for coming on and for taking the time to explain genomics to us. [00:09:18] Ella: Thank you, Florence. Thanks so much for inviting me, and it was a pleasure to be on the podcast today. [00:09:23] Florence: If you want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

A daily low dose of aspirin could significantly reduce the risk of bowel cancer in people with Lynch syndrome, an inherited condition that increases the likelihood of developing certain cancers. In this episode, we explore the findings from the landmark CaPP3 trial , hear from a participant living with Lynch syndrome, and discuss how genomics could help shift healthcare from treatment to prevention. Our host, Sharon Jones is joined by: Dr Katie Snape, Principal Clinician for Population Health at Genomics England Professor Sir John Burn, Professor of Clinical Genetics at Newcastle University Drew Hyde, participant in the Cancer Prevention Programme (CaPP3) Links: Listen to: How can genomics help us understand cancer? "I think knowing is always a good thing. And obviously, I wish I'd known earlier, and then, I could have taken more measures earlier on. So I think knowledge is definitely a good thing. And it would be great if more people could be tested or could find out if they were carriers at an early age, I think." You can download the transcript or read it below. [00:00:00] Sharon: Welcome to Behind the Genes. In today's episode, we'll explore the research which shows how a low dose of aspirin can halve the risk of bowel cancer in people with Lynch syndrome. We'll hear about the real-life impact of living with the condition, and look at how genomics can help shape a more preventative approach to care in the future. [00:00:20] I'm Sharon Jones, and to help us unpack all of that, I'm joined by our guests, Dr. Katie Snape, principal clinician for population health at Genomics England; Sir John Burn, professor of clinical genetics at Newcastle University; and Drew Hyde, a participant in the Cancer Prevention Programme, which is also known as the CaPP3 trial. [00:00:42] So to start with the basics, Katie, can you walk us through what cancer is in simple terms? [00:00:50] Katie: Sure, Sharon. So, our body is made up of cells. Those are the building blocks that, that make us as humans and other creatures and plants. And our cells need to keep dividing throughout our lifetime as our bodies are growing and working normally. [00:01:06] And so we need to have processes in place in our body where our cells can divide, but then also stop dividing when we don't need them to carry on dividing. What happens in a cancer cell is basically that cell becomes abnormal, and it doesn't follow the normal checks and balances and rules of cell division. [00:01:23] So it starts to divide and grow uncontrollably, and it can start to invade other tissues and obviously, that can cause serious consequences. [00:01:33] Sharon: We'll hear a lot more from Dr. Katie Snape in this episode. But before we move on, I just wanted to flag that there was an episode of our Genomics 101 explainer series with Katie dedicated to helping us get to grips with how genomics can help us understand and diagnose cancer. [00:01:47] Do go and check that out. We'll put a link to that in the episode description. [00:01:54] So the World Health Organization estimates between 30 to 50% of all cancers are preventable. So, Katie, when we talk about cancer being preventable, what does that actually mean? And what's an example of cancer prevention that people might already know? [00:02:11] Katie: Yeah. So some cancers are due to chance or just mistakes happening as our cells copy. [00:02:19] Other cancers are because there has been damage to the genetic information within the cell that can be caused by certain things that can cause damage to DNA. So for example, a sort of obvious answer would be skin cancer. Skin cancers can be caused by sunlight, the, the UV light in the sun, and particularly if we burn our skin or, or get sun damage to our skin, increases the chance of us developing a skin cancer. [00:02:44] So you can think of lots of other examples such as cigarette smoking and lung cancer, and so we know that there are a number of different risk factors that increase the chance of our cells developing damage and becoming abnormal cells and growing uncontrollably. So when we talk about prevention, we might think, well, could we reduce some of those risk factors and therefore reduce the chance of those cells getting damaged and becoming cancer cells? [00:03:10] So I gave the example of skin cancer. We might put sun cream on if we're going out in the midday sun, for example. That reduces the damage of the UV light onto our skin cells. Or we might help people to go into a smoking prevention programme or, you know, other risk factors, such as we know that being very overweight can increase the chance of cancer. [00:03:31] We might help people get into more exercise regimes or improve people's diets. So those are the sorts of things that we might do sort of for environmental risk factors. But we also know, particularly in this context, that sometimes people are born, they carry genetic changes within their cells that they're born with, that are inherited, that run through families, and those can also increase the chance of some cancers developing. [00:03:56] And for those people at higher genetic risk, then we might look to other ways that we might reduce that risk. We can't change the genetic changes in their cells, but we might be able to put things in place to reduce the risk for those individuals, and that might be medication, it might be surgery, or there could be other things that we might be able to offer. [00:04:15] Sharon: Yeah, and with that in mind, is there anything more, you know, that you can share about some of those risk factors that someone is more likely to develop cancer? [00:04:25] Katie: Yeah. So actually, the, the biggest risk factor for developing cancer is age. The older we get, the more times our cells have divided, the more chance there is of a copying mistake that, that, that can cause that cell to become abnormal and start growing uncontrollably. [00:04:41] And that's why cancer becomes more common the older we get. We obviously can't change our aging process. Then, as I've said, sometimes we're born with certain specific inherited factors that increase the risk. That might be one big high-risk genetic factor, such as having a cancer gene that's important for, for that process of cell division that isn't working properly. [00:05:04] Or it could be that we have multiple lower genetic risk factors that can kind of add up together to increase the risk. And those often interplay with some of those environmental factors that we've talked about, like smoking, for example, or weight, or alcohol or other things like that. So most cancers are due to aging, and then there's a sort of interplay of genetic factors, but environmental factors as well. [00:05:30] Sharon: That's really interesting to understand. And the focus of this podcast is sort of looking at kind of Lynch syndrome and what findings have come out around aspirin and having a low dose of aspirin. So I want to kind of explore what Lynch syndrome is and, and then bring in Drew to talk about his experience of having Lynch syndrome and how he got involved in the trials themselves. [00:05:49] So from what I understand, Lynch syndrome is a genetic condition that can make some people more likely to have the chances of developing into bowel cancer. And Drew, this is your opportunity to sort of talk about what that's been like living with Lynch syndrome. And, you know, I'd like to understand more about your story and how it came about that you discovered that you had Lynch syndrome, and to share with our listeners your journey. [00:06:13] Drew: Yep. So in my case, I discovered I had the colon cancer before I discovered I was a Lynch syndrome carrier Basically, at the age of 50, I noticed some change in my health. You know, I was becoming a little bit more tired. My bowel movements had changed or whatever. So, I went to the GP and the GP basically said, "Well, you're probably too young for cancer, so let's look at other alternatives." [00:06:37] And I had blood tests and I had low iron, so I was on iron tablets for three months and whatever. Then eventually I went back and finally the GP said, "Well, let's try a colonoscopy." And the colonoscopy revealed that I did actually have colon cancer. And then very quickly I had surgery and, uh, then following that, I kind of asked the question, "Well, why me?" [00:06:59] You know, I'm only 50, 51. Yeah. You know, why me? [00:07:02] Drew: And basically, I was told, "Well, it's probably genetics." And then I was referred to, you know, St George's and Katie and I had the test and discovered that I was actually a Lynch syndrome carrier, and that's why, you know, I'd got the colon cancer at the age of 50, so. [00:07:17] Sharon: I mean, that's quite a journey. I mean, how did you feel when you're already on one pathway and then having to kind of find out more, you know, what was your experiences? What was the impact on your life? How did you, how did you feel? [00:07:27] Drew: I think I was lucky in that I had a very good surgeon. I had surgery very quickly, so that was the first hurdle. [00:07:32] Then I had to go on to chemotherapy, and the chemotherapy obviously is far worse than any surgery or anything else that comes before or after. But having got through that, then I went through the St George's onto the Lynch syndrome system. So, the most important thing then really was to basically identify what that meant for me, but also because it was an inherited characteristic, what it meant for my family. [00:07:57] One thing that was interesting, and I say, you know, the, the GP was saying, "Well, you're too young to have cancer," is that there wasn't any history of cancer in my family, you know, looking at older relatives. So, you know, to be fair to the GP, that wasn't an obvious marker. So basically, yeah, it was let's, you know, find out what it means now going forward. [00:08:21] Sharon: So, can you just take us back to when you were diagnosed with Lynch syndrome? What sort of guidance were you given at the time about managing your cancer risk? [00:08:30] Drew: Well, following the surgery, I was given various statistics which were fairly grim on what your percentage survival rate were in three years, five years, 10 years based on the surgery, whatever. [00:08:39] And that was kind of a bit harrowing. But, you know, assuming I'd get through five years, I felt it was, my chances were quite good. As for myself living with, living with Lynch syndrome, that, you know, I was aware that having had the colon cancer, I then had increased risk of other cancers. So since then, I've been on a screening programme, and I have colonoscopies or gastroscopies every year or two years. [00:09:04] So that's been very good. So, I believe now that if any other cancers were to appear, I would probably know very early on because they would be detected through a screening process before they got to a point where they would be, you know, maybe too difficult to resolve, so. So that's-- I think the screening programme, has been very, very good. [00:09:23] The main issue for me was what it meant for my family, being a genetic thing. So very quickly, my children, who were teenagers at the time, were both tested, and they went through some counselling with Katie beforehand, you know, about what it would mean for them to get a positive or negative result. [00:09:42] Unfortunately, my daughter was tested as negative, but my son was tested as positive, so he's now on the same cancer screening programme, and has colonoscopies every two years. So yeah. The mystery really, though, is where I inherited it from because my father died when I was very young. My mother was in a care home at the time, and I wanted to get her tested. [00:10:07] And at the time, her GP wouldn't test her on the basis that she was unable to give consent. But fortunately, I had power of attorney, and we could persuade him to do the test. But she tested negative. So I'm assuming I inherited it from my father's side. But most of my grandparents on that side of the family lived into their nineties without any apparent cancers. [00:10:32] So it's still a bit of a mystery how I inherited it, but what was important for me was to know which side of the family I'd inherited it from because obviously with cousins and whatever on different sides of the family, I wanted to be able to tell them what the situation was. My brother also tested negative, which was a positive. [00:10:54] So at the moment, it's just my son and I that have the defective gene. [00:10:59] Sharon: I'm sorry to hear that about your son, but does it- [00:11:01] Drew: Well, well, I mean, he, you know, he has to go through a colonoscopy every couple of years, which, you know, obviously is not a pleasant experience. But at least he knows that, you know, the first sign of any problem, the medics will be aware of it, and he'll be able to react. [00:11:16] Sharon: Has it changed your outlook on life, having this window in possibly knowing stuff or not knowing stuff? How has that affected you and, and your son as well? [00:11:25] Drew: I think knowing is always a good thing. And obviously, I wish I'd known earlier, and then, I could have taken more measures earlier on. So, I think knowledge is definitely a good thing. And it would be great if more people could be tested or could find out if they were carriers at an early age, I think. [00:11:42] Sharon: Yeah. That is really important. And moving into about the trial more broadly, scientists have known that there's been a link between cancer and aspirin for some time, with fewer cancers observed in people who take aspirin. So coming to you, John, could you share a bit more about the history of inherited cancer research and how the focus of Lynch Syndrome came about? [00:12:02] Because this isn't new, is it? [00:12:06] John: No, absolutely, Sharon. And in fact, this story, my story in this space begins 40 years ago when I was one of the geneticists who set out to try and find the genes that we've just been talking about. At that time, the group of patients who were the most obvious to begin with were young people with a condition called familial adenomatous polyposis, or FAP for short. [00:12:26] And they'd get thousands of polyps in their bowel, and the only way to treat that was to actually remove the whole bowel when they reached adulthood, which is a fairly extreme intervention. And I was running, I was setting up a registry. We were trying to find the gene at that time, and we'd just found it, in fact, but we also were trying to find all the families. [00:12:44] And I'd taken over responsibility for all the genetic services in the north of England, in the North East and Cumbria. And we'd, I'd started identifying families with FAP, and we went to visit one of those families, and this was the kind of light bulb moment for me because I walked into the room and mum had had her colon removed, and her son, Jonathan, had just had his first colonoscopy at the age of 12, and it was clear. [00:13:07] And I was about to give them the good news, but as I walked in, I noticed that he had little bumps on his forehead called osteomas, little bony bumps. His mother had them just the same, and it was one of the features of this condition. So I knew he had the gene even though he hadn't yet got the polyps. [00:13:21] Sharon: Wow. [00:13:22] John: And it made me think, wouldn't it be nice if we could do something to prevent these things happening rather than just waiting for an operation? And as it happened at the time, I was leading the English end of a big study, which you'll probably be aware of, which we're, we're, we were doing the vitamin study on women with spina bifida babies, and we were just about to identify folic acid as a way of preventing spina bifida in pregnant women. [00:13:45] So I had these two thoughts in my head. Maybe we could set up a trial like this folic acid trial, and then one of my friends in Edinburgh said, 'Have you seen this paper from Melbourne?' Gabriel Kuhn had just done a big study looking at people with colon cancer. It seemed that people who took a lot of aspirin didn't seem to get as much bowel cancer in Melbourne as those who didn't. So that was the design set up. [00:14:08] We were applying to Europe for a concerted action, so we had to think of an acronym that began with CA. So I, I came up with Concerted Action Polyp Prevention. But then in 1993, just as we started that trial, we were involved in finding the first of the genes for Lynch syndrome. We had a big family in Northumberland where there were lots of people like Drew's family, and there were three generations of cancer in the family. [00:14:31] So CaPP2 was immediately born in my head. In 1999, we had our first recruit, and we recruited until 2005. We found, in total, 1,000 people in 16 countries to join in, and we gave them two aspirins a day or two dummy tablets. Two aspirins is quite a big dose, but back in my day when I was a junior doctor, we used to give many more tablets of aspirin to people with arthritis. [00:14:57] So two tablets wasn't such a big deal. Nowadays, it's seen as a very high dose. And it worked. Basically, to cut to the chase, when we looked in 2010, the people who were getting the aspirin were getting less bowel cancers. In fact, it was a 50% reduction. So the people who took two aspirins had half as many bowel cancers and fewer cancers of other types as well. [00:15:19] We realised, although, at this point, immediately we saw that it was working, we knew we'd need to do another trial to see whether a smaller dose of aspirin would be just as effective. So CaPP3 began, and the great news is that what we'll be reporting in the journals in the next few days when it gets published, is that the people who were taking CaPP3 aspirin in any dose were tracking exactly the same as the 600-milligram group in CaPP2. [00:15:46] So we're pretty sure that it works. We're pretty sure that the small dose is just as good. And the great news was that we had fewer side effects in that group. And so in fact, no one had to go to hospital for a transfusion or anything, you know, like that. Whereas in the 600-milligram group, we had a few people who needed treatment because, as you know, and everyone knows, if you take aspirin, there's a higher chance of having an ulcer that causes a bleed. [00:16:10] And that was always the anxiety. But people like Drew were courageous enough to take the chance because they knew we needed to know the answer to this. And of course, when you compare it to the risk of getting cancer, taking an aspirin is a relatively small risk. [00:16:26] Sharon: So, what were your kind of considerations when you were designing the trial, having that knowledge? [00:16:32] John: Well, the first thing is it has to be fully informed consent, which means that you have to explain to people what that risk is. The important thing about aspirin is that doctors have a much worse opinion of it than it deserves because if you work in a hospital, you'll often see people coming in who've had a bleed. [00:16:48] It's not always caused by the aspirin. The thing is, if you're coming with a bleed and you're on aspirin, everyone blames the aspirin. Right. About half of them would've happened anyway. In fact, the, the irritation of the stomach is much more of a problem in older people So in fact, the average age of the people in CaPP2 and CaPP3 was about 45, 46 when they started. [00:17:08] Drew was a little bit older, but, but people in that sort of middle age group are much, much less likely to get into trouble than people in their 70s and 80s. And it's people also who've had a history of ulcers that have a bigger problem. We also knew that if you had a stomach infection called H. Pylori, which is itself a risk factor for cancer, and about one in six people carry that bug, and we knew that if we fixed that with antibiotics, that would signifi

In this explainer episode, we’ve asked Jamie Ellingford, Lead Genomic Data Scientist for Rare Disease, to explain how genomics is helping us better understand rare conditions. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk . You can download the transcript or read it below. [00:00:00] Florence: How can genomics help us better understand rare conditions? My name is Florence Cornish, and today I am joined by our Lead Genomic Data Scientist for Rare Disease, Jamie Ellingford, and he is going to be sharing lots more insights about the topic with us. So, I guess before we begin, Jamie, it might be useful if you could explain what we actually mean by the term 'rare condition'? [00:00:25] Jamie: Sure. Hi, Florence. So, a rare condition we define as something that impacts one in less than two thousand people, and so that's something that occurs really infrequently in the population. But we know that collectively there's lots of different rare diseases. And so, the estimates are that it's about one in seventeen people in the population that are impacted by some sort of rare disease, of which we think there's over seven thousand. But research that uses data that we have here at Genomics England as well as other sources is starting to uncover more and more of these individual rare disorders. So collectively, as I just said, one in seventeen individuals, we think, is impacted by a rare disease, and that equates to almost three and a half million people here in the UK. [00:01:15] Most of these rare conditions, we think, have a genetic basis, and perhaps we'll explain a little bit more about what that means. [00:01:22] Florence: Yeah, no, it would be great to talk a little bit more about that actually. So as you said, most rare conditions we think have a genetic cause, but I think it might be helpful if you could explain what we mean when we say that something 'has a genetic cause'. [00:01:35] Jamie: Of course. So maybe we go back to kind of the basics and kind of how a person is first formed. So, at that point of fertilisation, where the sex cells from mum and dad join, we inherit one copy of our genome from mum and one copy from dad, and it's the order and the composition of these letters in our genome which makes it unique to us. Most of that genome is absolutely identical to anyone else in the human population. And a small fraction of it is unique to us and is a combination of things that we've inherited from our mothers and our fathers. And when we think about genetic causes, largely, we look at those differences. And so, what is it that's different in individuals compared to the wider population that could be driving these rare conditions? [00:02:23] Florence: So could you maybe explain a little bit more about how people's genetic material, how people's genomes differ from one another? [00:02:30] Jamie: So there's lots of different ways that we can observe these genetic differences. So some of them impact individual letters, and we, we may swap a single letter for another. [00:02:41] We can also remove small sections, so it may be that a run of three or four of these letters is deleted from someone's genome. But on the opposite end of the scale, we can also see huge changes in how that genetic material looks. So perhaps a good way to think about this is as a story. And so if our, if our genome is like any kind of good fiction story that you would read, then we can have spelling mistakes that impact single words, [00:03:09] that impact whole paragraphs, or some which impact whole chapters. Lots of these different types of genetic causes can give rise to genetic conditions. And so even the smallest changes, the smallest spelling mistakes in words, can still give rise to rare genetic conditions. [00:03:26] Florence: We actually have a previous podcast episode that explores that topic in a lot more detail. So if listeners want to check that out, it's called "Are genetic conditions always inherited from parents?" So obviously, Jamie, we spoke quite a lot about DNA and genetic changes there, and this episode is all about how genomics specifically can help us better understand rare conditions. [00:03:47] Um, but what actually is genomics as a field of study? [00:03:53] Jamie: So simply put, genomics is the study of the whole genome, or at least as complete a picture of the genome as we can possibly represent. And so in the case of rare disorders, we use genomics to try and understand what the genome looks like from an affected child. [00:04:12] And, um, in some cases, we're also able to look at the whole genomes of their relatives, so perhaps their mother and their father. And we use this information to best detect and best prioritise variants that we think are giving rise to their genetic condition. But how we've done that has evolved and advanced a lot over time, has gone hand in hand with these remarkable developments in technology. [00:04:37] And so a decade ago, maybe 15 years ago, the state-of-the-art technologies were to look for single spelling mistakes or to be able to survey complete genes. Nowadays, we can generate data for the whole genome, and we can do that fairly cheaply, we can do it quickly. And we rely on computational algorithms and the development of bioinformatic resources to be able to properly make sense of that data. And so there's, there's three key aspects of bioinformatics, this discipline of integrating informatics, computational technology, with biology. [00:05:17] And so the first is, having generated some data, can we appropriately find where in the human genome that data should map to? Having done that, can we detect these differences, these small or large changes in the human genome, for that individual? And finally, can we start to make sense of those changes? Can we understand whether they exist frequently in a population or they're unique to this family and predict what potential consequence they have on a gene's function? [00:05:47] Florence: Mm. So there's obviously lots of different components of genomics, but how can all of them help us better understand rare conditions specifically? [00:05:59] Jamie: So as we've already touched upon, most rare diseases have a genetic basis, and we think that that estimate could be something like 80% of rare diseases have a genetic component to them. And what we've seen over the past decade and further, is that genomics has really transformed the discovery of new genomic conditions. [00:06:20] And so being able to look at data from the whole genome has allowed us to understand new genetic, types of genetic changes, changes in new genes, which could cause these rare conditions. And what we've seen recently is that move and that transformation from genomics as a discovery tool to a tool that we use routinely and so essentially, we've moved this technology from research laboratories into the NHS and the UK healthcare system. We've really come a long way, and so, whilst we see that the amount of genetic diagnoses that we can find is really dependent on the specific disorders, broadly, we find genetic diagnoses for somewhere between a quarter and half of the individuals that are referred. [00:07:10] What that does mean is that there's still 50% of individuals out there that get referred to these services with a rare condition where we don't find an obvious genetic answer through the implementation of genomics within healthcare. [00:07:24] Florence: Do you have, um, a specific example you could share of where genomics has had a real impact in our understanding of rare conditions? [00:07:33] Jamie: So I think all of us that have worked in this space for, for a long time have our own individual examples. We're recording this in 2026, and over the past two years, there's been a flurry of discoveries of genes which don't directly encode proteins, that cause a certain type of rare conditions, and so we call these non-coding genes. [00:07:54] These genes have recently been described as a cause of kind of wide neurodevelopmental disorders, as a cause of genetic blindness, and there's ten at the time of recording, distinct rare conditions another example that I wanted to elaborate on is something that was really personal to me because it happened really early during my development as a, as a researcher and as a, somebody who looks at genomic data very early in my career, and really kind of had a profound impact on how I think about genomics and how it can be applied. [00:08:28] And so this was an individual who was referred with a certain type of rare condition. And through the analysis of their genomic data, we identified a genetic variant in a certain gene. At the time of testing, they were in their early teenage years, and when we looked at the scientific literature, what this suggested is that other symptoms were going to develop before the age of 20. [00:08:52] And so at this point, genomic testing had been done in a really critical window for that individual and allowed them to be referred to specialist centres, and to be managed appropriately, and that's really ended up in a good outcome. And what's becoming more and more frequent is the opportunity for genomics to inform enrolment to clinical trials, the development of targeted treatments, and we hope that in the next decade or so we'll see an increased flurry of those activities. [00:09:22] Florence: Yeah. So I guess, would the headline be that genomics allows us to see changes in the genome that maybe more traditional genetic tests wouldn't have allowed us to see, and then that in turn helps us with our approaches to rare conditions? [00:09:37] Would you say that that's accurate? [00:09:40] Jamie: So it certainly gives us that opportunity. [00:09:42] Florence: So I think we'll finish there, Jamie. Thank you so much for coming on, for taking the time to speak with us. It's been very insightful. [00:09:50] Thank you very much. A pleasure to chat. [00:09:52] Florence: If listeners want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. [00:10:03]

When people think of midwives, they often think about pregnancy and birth, but the reality of modern midwifery is far broader. In this episode of Behind the Genes, our guests explore the many different roles midwives play across healthcare, from clinical care and safety improvement to research and genomics. The conversation looks at how midwives are helping shape the future of maternity care through research, supporting families to make informed decisions about genomic testing, and contributing to studies like the Generation Study. Our host, Sharon Jones is joined by: Katie Handley - maternal and child health clinical lead for the Generation Study, Fiona Smith - research midwife for the Generation Study at Rosie Hospital in Cambridgeshire Jess Fletcher - safety and quality midwife at the Rosie Hospital and a participant on the Generation Study You can find out more about the Generation Study via the study’s official website . “ The more brave we are as midwives, and the more that we're willing to be curious about what we can do to improve our care, the better we're going to be at our profession. All midwives want to do is to provide safe, effective care that is what is in the best interest of that woman. We are advocates for women and for their families.” You can download the transcript or read it below. [00:00:00] Sharon Jones: Welcome to Behind the Genes. How is genomics changing midwifery, and what role are midwives playing in shaping the future of genomic healthcare? Also, do midwives just deliver babies, or is their role much broader than many people realise? [00:00:16] My name is Sharon Jones, and in this podcast we cover everything from cutting-edge research to real life stories in genomic healthcare. [00:00:23] Joining me today are Katie Handley, Fiona Smith, and Jess Fletcher. Katie is Maternal and Child Health Clinical Lead for the Generation Study, Fiona is a research midwife for the Generation Study at Rosie Hospital in Cambridgeshire, and Jess is a safety and quality midwife at the Rosie Hospital, and a participant on the Generation Study. [00:00:42] Together, we'll be exploring how midwifery's evolving, where research fits into clinical practice, and what genomics mean for maternity care now and in the future. We kicked off this one by asking Katie what roles midwives play day to day. [00:00:56] Kate Handley: I think when people think of midwives, they think of helping a lady to have a baby. [00:01:01] We're there for the birth, we're there to catch the baby, but it is so, so much more than that. We're there from the moment a woman becomes pregnant or even before that. We can help with prenatal, uh, preconception care. We're there all the way through the pregnancy, for the birth, and then afterwards as well, we'll look after the lady, her family, until, until we hand the baby and, and her over to the health visitor or to whoever's next in her care pathway. [00:01:25] But that's just looking at clinical midwives for the... that are involved directly in that particular pregnancy. There's midwives doing all sorts of other roles. I think I'm a really good example of that. So I am a clinic- I was a clinical midwife. I am a registered midwife, but now I work as a clinical lead, so I'm using my midwifery background and my midwifery skills in a research environment, but to help people who don't know as much about midwifery to implement a research study, and how we can make a research study real in a clinical environment. [00:01:59] So that's one example, but there are so many other things, and we have midwives doing screening roles and lots and lots of midwives working in research as well. [00:02:08] Sharon Jones: That's interesting. I've got a couple of friends who are midwives, and I would never have known, like, the extent and scope of their role. [00:02:14] Kate Handley: Yeah, I think people might be surprised to hear that you can be a midwife but never actually even see a pregnant person. So we have midwives that are academics, for example, or midwives that are lecturing at universities, midwives that are working behind the scenes in risk and governance and looking after the safety aspect. [00:02:30] Sharon Jones: That's amazing. I would never have known that. So Fiona, how has your role as a midwife changed over the years? Because you've gone through quite a bit of a transition, haven't you? [00:02:39] Fiona Smith: I have. Before I even became a midwife, I was, I was nursing. That nursing pathway was not academic, as we now have to undertake academic training to become a midwife. [00:02:50] So we... the training was very different. It was very hospital-based, and this is what you do, this is what we do. You would do some observation. You'd have a go. You'd get signed off. That really was my nursing background, and then when I started to explore midwifery, and it was much more academic, and that I was going to do the university pathway, I doubted that that would be something that I could actually even contemplate. [00:03:15] Moving forward 20 years, here I am. I've had various roles: community midwife, running birth centres, and then more recently, the last six years, joining a university hospital which has a, a, a big emphasis on research and academic training, brought in lots of students, medical students, and others. I saw some research that was happening at the hospital and became quite curious, took the plunge, and the last two years I've been working as a research midwife, which was a real surprise to me to find that this is where I am, and to actually be working on a genomic study is an even bigger surprise. [00:03:57] If you'd asked me 20 years ago that this is where I'd be, I'd probably have laughed and said, "No, that's not something that I could even be contemplating." [00:04:07] Sharon Jones: That's fascinating. It's fascinating, the journey you've been on and how midwifery and nursing training has evolved more broadly. So Jess, how does that compare with your own journey in midwifery? [00:04:19] Jess Fletcher: Similarly, actually, like off the back of what Katie and Fiona are saying, you do kind of go into midwifery thinking that your career is going to very much look like providing labour care and catching babies, which is a wonderful part of the job. And that is very much my background, is that I have been, like, a labour and delivery midwife, usually on the birth centre or in the community doing home birth. [00:04:43] So, and never in my wildest dreams did I think that I would pivot and go into something specialist. I think you k- ... Well, in my case, certainly, I kind of fell into it, quite literally, uh, because I broke my ankle and then had- ... to work from home for quite some time. I was offered to be off sick, and I was working at a new trust, and I kind of wanted to, so to speak, keep my foot in the door. [00:05:05] And I said, "Oh, I, there must be something I can do from home." And they set me up to do some auditing, which quite frankly, a few years prior I would've ... Yeah, you couldn't have paid me all the money in the world to do auditing. And then, lo and behold, I found it so fascinating, not just the process, but kind of seeing how that then would kind of implement us in clinical practice. [00:05:28] And now I'm a safety and quality improvement midwife. My office is on a birth centre though, so it does mean that I still very much work clinically. So yeah, so a similar story. [00:05:38] We're such a highly skilled profession that we can apply it in so many different ways. And now of course, I'm on maternity leave with my third baby. [00:05:46] Sharon Jones: Congratulations. [00:05:47] Jess Fletcher: And so taking a little, a little break, but really lovely to talk about it all today actually. [00:05:52] Sharon Jones: Yeah. Thank you. Thank you for sharing that. [00:05:53] So as mentioned, alongside clinical care, midwives are, are playing this increasingly important role in research. [00:06:00] And though it's something that people might not necessarily realise and they might not associate with the profession, I'd love to explore what that actually means in practice and how midwives have become involved in this space. So Katie, where does research fit in with midwifery today, and how do midwives get involved in that space, and is that something that all midwives are engaged with? [00:06:21] Or is it a more specialist kind of pathway? [00:06:23] Kate Handley: It can be a specialist pathway, but I think what's really, really important to realise here is that every single midwife is involved in, in research, whether they realise it or not, or midwifery care, has got to be evidence-based. Everything we do is evidence-based, um, because that's what keeps midwifery care as safe as it possibly can be, and we can only get that evidence base from doing research. [00:06:46] So even if midwives aren't taking part in a research study themselves, if they're not, you know, getting consent from people to do research studies, the care that they are giving comes from research that has been done in some space. Even if that's not within the UK, it's research that has been done. So research is incredibly important. [00:07:03] That's how we evolve, um, our care, how we evolve our pathways, evolve our guidelines is through that, through that research. [00:07:11] Sharon Jones: So can you talk to the audience about what is a research midwife versus a clinical midwife? [00:07:16] Kate Handley: So a clinical midwife generally is somebody that will have hands-on care during the antenatal and intrapartum or, or postnatal period. [00:07:24] A research midwife, often that will be someone who still works on a ward, in a hospital, but is helping to put research into place. So that may be running a study and taking consent from women to take to be part of that study, and then doing whatever the study needs. Or it can be actually conducting their own research, it can be writing, it can be an academic form of, of midwifery as well. [00:07:49] It's really, really important, and it really depends on the hospital and on the trust how much that research is incorporated into the clinical care, and sometimes it can be quite separate. But both very, very important. And the Royal College of Midwives are really, really trying to work on making research part of general midwifery care. [00:08:09] It's something that undergraduates need to do now as part of their, their degree, which all midwives have to do a degree to become a midwife. They have to do research. They have to be involved in research. Midwives in their first year of being qualified should still be having a research role and looking at how research can broaden their clinical skills, and it's something that should be going on throughout their entire career [00:08:32] Sharon Jones: Yeah, that's great. [00:08:33] Fiona, what does a typical day look like in your kind of research-focused role? [00:08:38] Fiona Smith: Firstly, just to say, when I moved from a clinical role into the research role, I thought I was going to miss that kind of adrenaline rush that does come with being a clinical midwife. And so I thought, it-- this is so quiet, it's just a really very different pace. [00:08:54] But actually, there are deadlines and things like that. So yeah, on a daily basis, it is really... it's a really busy day. [00:09:02] So we can be answering our emails and inquiries about research. We're liaising with the clinical team, so I'm involved in a screening study, so we, we need to collect samples. So we go and collect samples, we register those samples. [00:09:19] We're then approaching our patients or ladies that come in to have scans, or they might be in the antenatal ward. We liaise with the community midwives who might have people that want to take part in the study, so we do a lot of communication with the women through that way. [00:09:38] And having the background as a midwife, having that holistic approach has really, really broadened, you know, and really helped support my role as a midwife. Having-- transferring those skills has been incredible. [00:09:53] Sharon Jones: So what kind of studies do midwives support? [00:10:03] Fiona Smith: So apart from the genomic studies, uh, because a, a lot of genetic-based studies are going on within our trust. Where they're looking at trying to understand why things happen and see if there's a genomic h- component that might be attributed to conditions. We've got observational studies where we use lots of questionnaires to ask patients about their experiences. We've got interventional studies, so that could be testing a new drug or an interventions, just testing something that might work and, and might build that into that evidence base to - [00:10:32] You know, to put into practice. I'm really surprised at the portfolio of, of studies that is available. So they could be, um, not just maternity-based, but the obviously obstetric-based and studies, and we do a lot of gynae studies as well, so we work alongside the gynecologists. [00:10:51] Sharon Jones: So Katie, genomics is becoming more visible in healthcare. How is that showing up in maternity care more broadly? [00:10:58] Kate Handley: So I think what's really important to note here is that genomics has always been really important in, um, maternity care. [00:11:04] It's just that midwives potentially didn't know that they were doing it. Um, so from the very moment that we book a pregnancy, so when, when a woman has her first appointment at, you know, 8-10 weeks, we're already using genomics to plan her, her care. So we're asking about family history. We're asking about a predisposition to, um, heart disease, for example, or heart conditions or diabetes, or things that we will then use to plan a, a pregnancy going forwards. [00:11:30] We're looking at, yeah, family history. Uh, we're doing screening, antenatal screening, which, uh, some of the tests there are genomic based. And then after the 20-week scan, for example, if we find some sorts of congenital abnormalities, we can use genomic testing then to find out what, what is potentially wrong with the baby and what we can do about it. [00:11:50] And then moving forward throughout that pregnancy, genomics is also really important in bereavement care. So if there's a history of multiple miscarriages, for example, or if a baby is stillborn, we can use genomic testing to find out any reasons for that and to hopefully improve, um, care for that woman going forwards as well. [00:12:08] The big thing that's going on at the moment for genomics in maternity and midwifery is, uh, newborn screening At the moment, our newborn screening is looking for, uh, nine or 10 different conditions, um, which are very rare, but do have some treatment if they are caught early. What we're doing with whole genome sequencing, where genomic testing is looking to see whether we can find a much larger range of conditions much earlier in the baby's life to see if we can improve outcomes for those babies. [00:12:38] And so that's a huge role of genetics. Yeah, absolutely. [00:12:41] Sharon Jones: So Fiona, how confident do midwives generally feel about discussing genomics with families, even though Katie's just said it's not sort of nothing new and it's always sort of been there, maybe badged differently. How do you feel that midwives feel about talking about it when they are talking to families? [00:12:59] Fiona Smith: They probably don't feel, you know, very confident speaking about it. And I definitely wouldn't have been able to speak confidently in a comm- as a community midwife, uh role. But what, what is great about the hospital is that we know that they're where to refer to. So we've got the fetal medicine midwives who are available at any point to talk us through what to say to women or to help us, and the screening team are really useful and are on hand to, again, help us navigate that and what to, you know, what to say to parents. [00:13:36] We've got a really good patient record system as well, so we should, we, you know, the notes are very accurate. We should be able to, uh, follow through from what the parents have been told already, what their journey looks like. So although we're not 100% confident, but I think the students coming through, they're going to have res- acquire a lot more knowledge. [00:13:59] And also our midwifery standards imply that genomics should be part of that everyday conversation that midwives are having. So although it isn't something that's familiar within our parlance. I think going forward, I think it definitely will become much more mainstay, if you like, just- [00:14:20] something that we will be naturally talking about because you know, let's face it, genomics is here. I want to say being part of the Generation Study team, because I'm quite visible and everybody seems to know me because I've, I've transitioned from one role to the other, you know, we are visible. I'm stopped quite a lot, and midwives are asking the questions and, "Well, why?" [00:14:43] You know, "Why is it important?" Just even to be able to talk about, you know, that we've, we're building up a database, data that's going to be used for future reference. Being able to have those conversations with, with the midwives now will really help that confidence. It's something that I didn't think I'd ever have a conversation with. [00:15:02] I don't have very deep conversations, but I know where there are people if I do need to get those answers. [00:15:09] Kate Handley: No, um, I think going with what, what Fiona says, I think it's really interesting that pregnancies generally now are becoming a lot more complex. Um, we're seeing a lot more high-risk pregnancies, and I think that we will find that, that women and their families, their knowledge of genomics is probably going to increase as well because we're going to see genomic testing more widely in, in healthcare, and that's going to have to then flow through into maternity and into midwifery knowledge because women are coming in with more of a baseline knowledge as well. [00:15:40] And when we're dealing with more complex pregnancies and more high-risk pregnancies, genomics is a huge part of that. We, you know- Mm ... because we're going to be looking at things like pharmacogenetics, where we can see what kind of treatments are going to be best for these women and how that can then impact on their pregnancies. [00:15:56] I think epigenetics is becoming more and more talked about and more interesting in maternity, you know, and it's really important that midwives are aware that we've been speaking for years about the impact of smoking, alcohol, all of the outside factors on a pregnancy. But when we actually consider that from a genetic point of view, and that these genetic changes could potentially then be feeding down through generations, it brings a whole new level to the, to that aspect of maternity that, that midwives do need to know about. [00:16:27] So I, I think Fiona's right. I think that there is a lack of confidence when you hear the word genomics, but as soon as you explain what genomics actually means, then that confidence can be boosted. And I think that as we go forwards, there's so much work being done in the training and education systems for universities, for midwives that are already practicing. [00:16:53] We're really trying to, to improve that confidence and competence. Within the Generation Study, that's something that we're working really, really hard on, is to make sure that we're giving all the really appropriate training to the midwives that are involved in it, and that's not just the research teams that are, uh, that are asking consent from the participants, but that's for the wider team as well to, to help the, the midwives who are taking samples, for example, understand why they need to take that particular blood sample, the importance of taking it at the time,

In this explainer episode, we’ve asked Kate Stanbury, research midwife on the Generation Study, to tell us more about the vital role that midwives play. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What does a midwife do? My name is Florence Cornish, and today I'm joined by Kate Stanbury, who is a research midwife working on the Generation Study, and she is going to be explaining the vital role that midwives play. So, to start off with Kate, I'm sure that most of our listeners will have heard of midwives before or maybe even like come across them in healthcare settings, but it would be good to hear from you more about what a midwife actually does. Kate: Yeah, absolutely. So, a midwife is someone who provides care and support to birthing people and their families during pregnancy, labour, and after birth as well. A lot of people just think of midwives as delivering babies, but we do a lot of other stuff around that as well. There are lots of different types of midwives as well, so we've got community midwives that might come out to your home and see you and your baby. We've got specialist midwives who might have a certain medical condition that they're experts in. And then we also have people like myself who are research midwives as well. Florence: So, you talked about a couple of different types of midwives there. Could you tell me more about the specific type of midwife that you are? Kate: Yeah, so a research midwife, as the name suggests, does research, so I also look after women during their pregnancy as well. A lot of the research that we do relates to sort of high-risk pregnancies, and so we approach women for specific research studies that might have a particular characteristic that we are investigating. We also recruit patients to these studies. We look after them during their pregnancies when they're taking part in the studies, and then we follow them up after their birth as well to collect data and see if what we've done as part of the research has had an impact. Florence: And so you are working on the Generation Study, and if any listeners want to learn more about that, then they can check out our previous Genomics 101 episode, What is the Generation Study? Kate, could you tell me a little bit more about what led you to become a midwife? Like what was the journey that you took to get to this point? Kate: Yeah, so I started my degree in midwifery straight out of college. So, I was quite young at the time, I was 18. I went to university, did a three-year degree to get a bachelor's of midwifery. That is probably the most common route that people go through in terms of to become a midwife, but some people choose to do adult nursing first, and then they can do a conversion course into midwifery, which is about 18 months long as well. So that's usually the most common route. I was sort of drawn to the occupation because one of my close friends, her mum was a midwife, so I used to see her in their lounge. They used to have lots of cards and things that she would display from patients that she'd looked after, which was really nice. Florence: And so what makes you passionate about working in the Generation Study and what motivates you in your role? Kate: I think being able to have an impact on how we can improve care, I think that's really important. Obviously everything that we do is evidence-based, so that's what really drew me to become a research midwife and being able to take part in research studies that we can look back on in the future and say, “oh, I was part of that, and because of that we've been able to improve the lives of families and babies going forward.” That's really important to me. Florence: Yeah. And, and just building off of that, have there been any specific moments that have like stood out to you during your time working on the study? Kate: Yeah, I think being able to see it from its starting point, so as a research midwife as well as working on the Generation Study. I sort of see people in clinics, I tell them about the study and then they might sign up to it. But then the other half of my role is a re regional results coordinator for the Generation Study. So I might then see that patient come through to me with a condition suspected result, and being able to follow that family through their sort of patient journey, from consent taking part in the study to getting their baby into NHS care, that potentially we might be able to give treatments really quickly for a baby that might have a really rare genetic problem. And being able to see that that process works really well and improves those outcomes for that baby and that family. That's really, really something that's amazing to see and what I'm really looking forward to in the future as well. Florence: Yeah, I can imagine that like getting to experience the kind of like end to end, like see it. Kate: Yeah, absolutely. Yeah. Florence: Super cool. Kate: We don't often get to follow the babies up in my line of work, so it's really nice. Florence: Yeah. Yeah. I'd also be curious to know has being involved in the Generation Study changed how you think about the space? So whether that's genomics or research or even your role as a midwife, do you see any of those things differently now? Kate: Yeah, absolutely. I think before I started this role with the Generation Study, genomics was sort of there, but I didn't really know the full details and like much in depth knowledge about genomics and how that could impact on people's health and their pregnancies and their health going forward into the future. But since doing this job, I think it's really opened my eyes to how much of an impact it can have and how much I think it could potentially improve the lives of generations to come. Florence: Well, thank you so much, Kate. I think we'll finish there, but I really appreciate you taking the time to come on our podcast. Kate: Thank you. Thanks for having me. Florence: If you want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

In this episode, we celebrate 10 years of the Participant Panel and explore how genomic research is being guided by patient and participant voices. Made up of people who have consented for their genome, or the genome of their loved one, to be included in the National Genomics Research Library, the Panel plays a vital role in shaping how research is designed, how data is used, and how genomics is communicated. From influencing policy discussions to to advising the Genomics England board, their work helps ensure lived experience is embedded from the very beginning. Over the past decade, the Panel has driven meaningful change. From advocating for greater transparency and accessibility, to challenging how the genomics community talks about genetic conditions. But beyond the impact, this episode focuses on the people behind the work: their motivations, experiences, and the realities of representing a wider community. Our host, Sharon Jones is joined by: Kirsty Irvine – Chair of the Participant Panel and member of the NHS Genomic Medical Service People and Communities Forum Lisa Beaton - member of the Participant Panel, panel member for the North East and Yorkshire GMSA and research and development for Harrogate Hospital Foundation Trust Frances Allan – member of the Participant Panel and member of the following: CRUK Women+s Cancers PPIE at Cambridge MHRA Yellowcard Biobank Northumberland NHS health forum Ovacome Healthforum IMPRESS cancer diagnostic tool study participant You can find out more about the Participant Panel in our recent Genomics 101 episode which Lisa featured in, titled ‘ What is the Participant Panel? ’, and you can read about their timeline of achievements over the last 10 years . “One of the things as participants that we're always really keen to get across, particularly to the scientists, is that behind every piece of data is a face and a name” You can download the transcript , or read it below. Sharon Jones: This time on Behind the Genes, we'll be celebrating the 10th anniversary of the Participant Panel, and we'll discuss how genomic research is being guided by patient and participant voices. The panel is made up of participants whose data is held in the National Genomic Research Library. They help us to put lived experience at the heart of our work. My name is Sharon Jones, and in this podcast we cover everything from cutting-edge research to real-life stories in genomic healthcare. Joining me this time are Kirsty Irvine, chair of the Participant Panel, and Frances Allan and Lisa Beaton, who are also both members. Collectively, they wear many hats for a range of organisations, which are listed in the episode description. As you'll hear, this one is all about people power. So back in 2016, the Participant Panel was in its infancy, with 12 founding members bringing lived experience of rare conditions. The idea was straightforward but radical: that the people whose genomes were being sequenced should have a real say in how the work was done. Over the decade since, the Panel has shaped some significant changes, from pushing for a service that let participants track their own samples, to publishing a language guide that changed how the genomics community talks about genetic conditions and disability. They've navigated the pandemic, welcomed new members and, in 2025, launched their first formal strategy. This year they mark their 10th anniversary, and today we're hearing from some of the people who've been part of that story. So welcome Kirsty, Frances and Lisa. So what was your reason for joining the Participant Panel? And I will ask Frances that. Frances Allan: Hi Sharon. I joined the Panel back in 2023 following a cancer diagnosis, and as part of that investigation I was fortunate enough to have a whole genome sequence performed. And they also asked would I be interested in taking part in a panel who look after this information, and I ticked the box and then thought no more of it. And then a month or so later I heard from the then Chair, Jillian, um, and had a chat about genomics and joined the Panel, and it was a very good decision that I made. Sharon Jones: Did you have any kind of expectations? What were your early thoughts when you kind of accepted? Frances Allan: Not many thoughts. So I was in the middle of my chemotherapy treatment, but one of the things that really stood out: when I signed the consent form, I said, well, of course I would do that. And the clinician consenting me, said, actually, not everybody does. And I thought, well, why would they not want to do that? So I was really interested in finding out about that. I had no idea how influential the Panel was, and that was great to discover as I became part of it. But seeing the breadth of the research and the knowledge already gained, compared to my rudimentary A-level Biology from many, many years ago, gave me incredible hope, um, and really helped me through a very difficult, difficult time. Sharon Jones: Yeah, that's, that's amazing. It's amazing that you could kind of think in that way whilst you were actually going through the treatment itself. I mean, how did you split yourself in that way? Frances Allan: I think it gave me a sense of, of purpose. So at the time, I'd, I'd stopped working to have my treatment and I was a, a vet previously, so I was used to thinking about medical things and problem solving, and it, it filled a, a void in my life. I had no idea I'd be able to contribute to it. I thought, well, I'd learn something from it. But, you know, the, the Panel is managed very well. Kirsty's a fantastic Chair. Everybody gets an opportunity to speak, and the attendance can be in person. And I've done most of them in person. When I was poorly I attended an online meeting, but even that is managed so well that you get a chance to speak up. If you're not feeling well enough, then you can, you can add it to the chat or email. So it's very, very inclusive and a very supportive environment, as well. Sharon Jones: Yeah, it sounds like a, a very safe space to be in. And Lisa, what was your reason for joining the Participant Panel? Lisa Beaton: I think it was sort of one of those, bit of a light bulb moment for me thinking, yeah, I could do that. I'm not quite sure why I felt I was qualified to do that, but my reasoning is slightly different than Frances. So I joined the 100,000 Genomes Project back in 2015 in respect of one of my children who has an undiagnosed, thought to be neuromuscular, syndrome. Um, so myself, my husband and our daughter recruited for genetic sampling, and over the years I've sort of taken a keen interest in all things genetic and genomic related, followed on kind of various social media platform. And I think if memory serves, I saw an announcement or an advert stating, do you want to be part of the Participant Panel, clicked on the link and thought, this is something that really resonates with me. I've served with different hats on different kind of participant groups and speaking events, and it's something I feel really, it's an overused phrase, but I do feel really passionate and strong about it because, you know, we are the people who are the front and centre of this, because it's our genetic information. So I applied, did a bit of a kind of resume of myself, um, then had huge imposter syndrome and thought, oh, that'll be the last I'll ever hear of that. And uh, actually had a really lovely interview with some of the then, uh, members of the Panel and must have said a few of the right things, 'cause here I am, three years down the line. Sharon Jones: That's amazing. Has it lived up to your expectation? How has it, how has it helped you get through what sounds like a really challenging time? Lisa Beaton: It's, it probably sounds wrong to say I, I didn't really have an expectation, but I joined it really just wanting to kind of know more and see if I could find out more details, more information, kind of more genomic discovery, and hope that I could give something back, if that doesn't sound too cringey. I think one of the things I'm always really keen to say is that you don't need to be a geneticist. You don't need to be a scientist. You don't need to kind of have lots of scientific information. And I will confess that the very first meeting I went to, I did come away thinking, I think I probably only understood about one word in three. But three years down line as I say, I'm still here, and it's been good to challenge myself and to explore kind of things that I don't know information about, but also I found that there are areas that I can definitely bring lived experience to and, and hopefully a voice for people like myself and my family. Sharon Jones: Yeah. That's so important. It sounds like you've become a bit of an expert by, uh, experience there. Has your vocabulary improved in the last three years? Do you know more words now? Lisa Beaton: Yes. Uh, I've, I have to remind myself not to use an acronym. It's one of my pet peeves. You know, when you're, you're in a, a meeting and terminology or, or vernacular, that is not necessarily something that people would use day-to-day, and I think lots of you know, you don't, don't have to be genomics or genetics to, um, using acronyms for things. It's something we all need to remind ourselves that just because you know that expression, somebody else doesn't. So it's really important to kind of keep that at a, a lay explanation so that everybody understands it. Um, I think particularly with quite heavy subject matter such as genomics and genetics, there can be a tendency otherwise for people to feel that it's not for them. And of course it is, because it's about our own personal data. Sharon Jones: Yeah, absolutely. And, um, and coming to you, Kirsty, what were your kind of motivations for, for joining the Participant Panel? Kirsty Irvine: Well, it's been quite a long journey for me to find myself on the Participant Panel, so I and my family, we were all consented into the a 100,000 Genomes Project back in 2015. But from that point, I then spent nearly 10 years chairing committees at NHS Digital and then NHS England, focusing on health data access. And I remember talking about the 100,000 Genomes Project at my interviews for those roles. I then went down a different path. And in those roles I was very much wearing my solicitor's hat. So I was thinking about governance and risk and were we complying with the precise wording of the legislation. And then when the chair role came available, I had a number of people sort of forward it to me saying, I think this would suit you. I think this would suit you. And at that stage, I was aware of the Panel because I'd met the fantastic former chair, Jillian. Um, so I'd seen Jillian at various conferences and meetings and things, so I was well aware of what the Panel did. I was well aware of the Panel's standing. It was probably the only participant panel that I was aware of in my work with NHS Digital, NHS England. And then I realised, you know, I wanted to be closer to the people behind the data and I wanted to do something more active. I wanted to bring a bit more of myself. Because when you're chairing a very formal committee, at NHS England, you, you can't talk about the time that you resuscitated your child at home, you know? And on the Panel, you know, my very first meeting, I, I met someone, someone whose child had, you know, been fed with an NG tube for a number of months. You know, I met someone else who had resuscitated their child, you know, and all of a sudden I could bring more of myself to my colleagues and, and find a real community. So for me, joining the participant panel was a way of shifting the perspective, but to also bring that experience with me because I, the roles at NHS England, you know, from a governance perspective, I couldn't continue chairing those, you know, board subcommittees forever. But I didn't want that knowledge to just sort of disappear. So for me, I'm really delighted that I've, what I hope, what I hope is a good fit. I feel it's a good fit. So that, that's been my journey to the Panel. Sharon Jones: Yeah, that's, that's so interesting. And I guess having that space to kind of be yourself, and having understanding because of your lived experience, brings a lot of value to the role that you're doing now in a way that kind of is different when you're in your previous roles of NHS Digital, because you had to be a bit more, kind of stand back from it and, yeah. That's so interesting. So, what has it been like being part of these groups? You know, the ones that you kind of, you're involved in a lot of things, and we'll list them in the, in the web description. And how has it kind of affected your life, essentially, because it's not the kind of average thing that people are involved in. Frances Allan: So it's been an incredible, I think as Lisa alluded to, incredible learning curve. We've learnt so much. But the team at Genomics England are endlessly patient and very skilful at passing that information on. And we have access to the leading researchers, the clinicians that are involved in genomics. And they're happy to take any question. And the questions, however silly, there's no silly question. They're happy to answer that. And so we learn every time we attend a meeting, we have quarterly meetings and that can be in person or online. Um, but we also have regular lunch-and-learns. So if there's somebody we want to speak to or find more about their specialist area, they'll come and have a, a chat with us. And then we have half of it, them chatting to us and half us, us. Us asking them questions and, and challenging them. Um, so it's very, very informative and then learning from each other. And as Kirsty was saying, you know, this is a, a group of people who've, who've dealt with an awful lot of unique situations and they're happy to, to share that and pass on the information. It's a, it's a great place of learning. Sharon Jones: Lisa, would you agree with that? How it been for you? Lisa Beaton: Yeah, I would definitely echo everything that Frances has actually said there, and I think it's a very humbling experience, as well. Ostensibly, we are a, a collection of individuals who have all been brought together, um, purely because of, uh, our genomic interests. And whether that's for our families, you know, as, as parents, as in my case, or in somebody like Frances' case, who's obviously a participant in her, in her own right. And although there are kind of many differences in our stories, there's also a lot of similarities. But I think what's really interesting, very precious, is that the staff at Genomics England, obviously they range from, you know, there, there's so many different kind of areas from the, the comms, the scientists, etc., but everybody is really interested. They want to know your story, who you are, why you are there. There's a real kind of inclusion focus on that. And one of the things as participants that we're always really keen to get across, particularly to the scientists, is that, you know, behind every piece of data is a face and a name. And I think they really make that felt when they're chatting to us. You know, we go in and, and there, there's people who are there from governance sides for how the data is accessed by other parties. There's people there who are the science technicians, etc. There's people who are dealing with the administrative side of things, but every single person that I've encountered wants to know more about you, what you are there for. And that is, is very, very precious. And as Kirsty also alluded to, a lot of us have been through some really quite traumatic experiences. It, it's not my place to speak of others' journeys, but you know, there, there are, uh, bereaved parents and family members among us. And so we are sharing very precious raw material, emotions, experiences, and that is very powerful, as well. And I, I think the Genomics England staff never forget that. They seem to bear that at the forefront of their, their communications with us, always. Um, and certainly Kirsty and Adam and previous chairs, uh, of the panel, that inclusivity was entirely throughout every dealing we had with them. Sharon Jones: It's very humanising and I think that it's humbling for us who work here that that's always at the forefront of our mind, that this is why we kind of get up and go to work every day, because of that human element. And it's not just a data point. There is a whole family, a story, a history, and that's, that's so important to us in the work that we do. Kirsty, did you want to add your point on this as well? Kirsty Irvine: I've probably got two points I wanted to raise. One was just to draw out what Lisa was saying, is that it can be complex being a Panel member, because the story you're bringing often isn't just your own. In my family, we've got a real, we've got a whole range of genetic differences and conditions that, you know, across the extended family. And so when I speak, I'm often drawing on experiences that aren't solely mine to share, and, you know. So I think that's something that for some on the Panel, we're sort of, we're, we're being quite careful to think about what we're saying, and if we're speaking in the public domain, we might be talking about it in more general terms. So that's, you know, but there's not a single right way, and there's room on the Panel, everyone, for the people who can and, and as Lisa talked about, you know, the, the most acute situation is where someone's bereaved, you know. And it's, so everyone's got different, you know, different experiences. But that, that, again, coming back to the positive side of things, one of the biggest things to me about being on the Panel, what it means to me, is being part of a wider community. I mean, one of the other things that, Sharon, I don't know if I can sort of segue onto this about, you know, the opportunities that have arisen? Sharon Jones: Yeah, absolutely. I'd love to hear more about that. Kirsty Irvine: So one thing that really stands out for me was the opportunity to speak directly with, um, Associate Health Minister Ahmed about, and his policy team. So we went to the department, Adam and I went to the Department of Health, and it was about the use of GP data in consented research cohorts. So getting the GP data into the National Genomic Research Library. So even though there's consent, up until now, that GP data, that tranche of really rich data, hasn't, hasn't gone into the NGRL. So I'll use that abbreviation now that I've used it in full. And so what was really unique for me was that I'd seen it from multiple angles because I'm participant in the 100,000 Genomes Project, so I'm a cohort member. I then worked on the consent review for NHS England. I then sat on a, the consent review assessment committee with, you know, a multiparty group. And then, because I was on the panel, I got to see things full circle. I was then invited to, to go and meet with, um, Minister Ahmed and, and advocate for the use of this GP data. And that really matters because something, you know, there's such important information sitting in that GP data and it wasn't a given, it was not a given that the government was going to the direction that allowed that data to go into the NGRL. And so we were able to talk about how we really wanted that data to be used. And now, going forward, you know, something as simple as BMI or for example, if a, if an individual's coded for a neuro, neurodevelopmental condition like autism, sometimes that data actually only sits in the GP health record. It's in primary care only, so it's not necessarily in the hospital records or other records. And so this is really, really valuable data for, for researchers. And so that was something that was a really special experience, just being able to see that come full circle. And I felt like it's a really tangi

In this explainer episode, we’ve asked Lisa Beaton, Panel Member and Parent Representative for SWAN UK, to tell us about the Participant Panel. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What is the Participant Panel at Genomics England? My name is Florence Cornish and today I'm joined with Lisa Beaton, who is a Parent Representative for Syndrome Without a Name, Swan UK, and a member of the Participant Panel. And we have a special episode today because it is to celebrate the 10th anniversary, so a decade of the Participant Panel at Genomics England. Lisa, I think it would be good to start with a quick rundown of what the Participant Panel is. If you had to describe it in a few sentences, what would you say? Lisa: Ooh, that's tricky actually, to cram all our wealth of expertise and knowledge into that, I guess in just a few sentences. But essentially, we are a group of lay people who have all contributed by way of being on genomic studies, such as the 100,000 Genome, for our data to be held in the NGRL, the National Genomic Research Library. We may have joined because our children or another family member have a disorder or a syndrome or a condition that requires further genetic testing. So, there are panel members who represent from different cancer communities, there's panel members who have connections with rare disease, and then there's panel members like myself who come from the undiagnosed community, where we joined to essentially try and find a diagnosis in respect of our daughter. The majority of us don't have any kind of medical background. We're all just individuals who collectively are really interested in where genomics and genetics is going to take us in the future. But probably most importantly, we all feel a sense of responsibility to ensure that there's equity of access, to diversify, to basically ensure that the lived experience of real-life people become more than just the data point to the scientific and research community. We, we are real people. Florence: Yeah. And could you explain a little bit more about the practical role of the panel? So what you aim to do as a group and what it involves to be a part of it? Lisa: Certainly. So as a panel, we meet either in person or on Teams approximately four times a year. So quarterly. We also get to listen to what we call 'Lunch and Learns', which have been absolutely fascinating. It's different people from different areas of the scientific and research community who will come along and talk to us about their latest discovery or what new things have been found. What's in pipelines, what we can be looking forward to. There's all sorts of different aspects of that. So currently a project that's been quite well known in the news is the Generation Study, the study of newborns. There have been research interviews and meetings around cancer studies. It's really exciting actually because every time there's something kind of new to learn or to see where progress is going, and that is just, I guess that's what most of us are there for, really just to see it in action. The role of the panel really is there to hold accountability, to ensure that, you know, data is being kept in a safe and secure manner, to ask any questions that we have about that. I think probably, we are all just members of the public, so our interests are widely there to ensure, you know, we're representing what we feel we would want to know, and therefore, hopefully in connection with what other members of who have kindly donated their genetic information and material towards studies so we, we can hold that agency for them and just to get more information, knowledge, share that out there with power. Power to the people, as it were! Florence: I'm interested if there's anything in particular that comes to mind that the panel has achieved that you are especially proud of, or that you are the most proud of. Lisa: Again, I think to squash that into just kind of one or two sentences is probably impossible, because there's so many things that panel members are proud of. One of the things that has definitely, we feel made a huge difference is the Plain Language Guide. We are absolutely adamant that, you know, everything should be as clear and easy to understand as possible. It's all very well having all the, the science and researchers who, you almost speak like a different language. For us, to get that passionately back to everybody who, who can be involved at different levels. You know, if you've contributed your time, your information, your DNA to research, then everybody who's done that, whether they speak English as a first language or second language, or if they have any kind of say, learning disability or just different socioeconomic experience, et cetera, it's really key that across the board everybody can, can access the language and terminology that is used around genetics. To summon up a point that has been used time and again, but is so, so crucial: nothing about us, without us. Florence Cornish: I can confirm, I'm a very big fan of the Language Guide. I use it all the time, I share it all the time. It's amazing, and you should be very proud of it. Lisa: Well, we definitely are. When I first joined the panel, one of the things I found really hard was I came into a room and I already had a bit of imposter syndrome. There were lots of terms being flung around in kind of, and acronyms. It's something we all do in everyday life, and you know, the more used to them you are the more you use them. But actually it's to go back and remind ourselves what those are. You don't want to be sort of 10 steps behind because you're constantly having to go back and, and look something up. So if you've got that guide there with you, if we ensure that everything is written as plainly and simply, whilst not dumbing anything down, just ensuring that it is accessible, that's incredibly important. Florence: Yeah, completely. So it's been really great to hear about what the panel does and, and the vital role that they play, and you've given a really great example there. But I thought it might also be nice to hear about what being part of the panel has meant for you and how it's impacted you just as a person, I guess, if you feel comfortable to share more about that. Lisa: Yes, definitely. So as I said, when I joined the panel, I did have a bit of imposter syndrome. Um, I don't have a medical background. I've gained 17+ years of medical experience because of our undiagnosed child, and I suppose I've gleaned quite a lot of information along the way, but clearly I'm not a geneticist. I'm not a doctor. I know what I know and I'm comfortable with that. I think joining the panel for me gave me back some of who I am as a person. Over the years, I've been 'mum' a lot of the time. Medical professionals in particular face-to-face, utilise that term. And I know it's not meant in any kind of patronising way, but being part of the panel has, has made me become sort of myself as a person again, I'm more than just 'mum'. It's enabled me to meet with fellow parents and caregivers and kind of share that common bond. Although we all come from different pathways and walks of life, be that the cancer pathway or the rare disease pathway, or the undiagnosed pathway, or in our case a combination of rare and undiagnosed, we share so many different things in common and our experience of commonalities, even if we've come about it from a different pathway, and that gives agency and strength, I think to us as individuals. We know what we are going through, that lived experience, that real voice really brings it back and I know from chatting to members of Genomics England and being at different networking events that they really hear us when they meet us, we are so much more than just the data. Florence: Yeah. Thank you for sharing that. And in connection to that, I just wanted to finish off by giving you the opportunity to say, is there one thing that you wish people knew about patient advocacy in general? Lisa: Yes, come and join us would be my message. We need more people. We definitely need more diversity. We want to hear from everybody and anybody, you know, genetics, genomics affects all of us. By 2035, I think it is, that it's predicted that more than 50% of medical such encounters will be with a genomic connection. And so to ensure that, you know, we are representing all members of communities across the board, we need more and more people particularly people of different backgrounds, would be something that I would be very keen to see the panel kind of move and diversify into. Florence: And so, for anyone listening that does want to get involved, how would they go about doing that? Lisa: So, I think there's probably quite a number of ways. I personally saw some information on Facebook. They're across different social media - X, Instagram, et cetera. So, there's definitely more information there. Obviously type in their website, Genomics England, and there's different links on the pages there. And come, come and join us. We're a very friendly bunch. Florence: Thank you so much, Lisa, for sharing more about the Participant Panel and the vital role they play and have done for the last 10 years. Lisa: Thank you so much for inviting me to be a part of this. Florence: If you want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

In this episode, we explore how individualised medicines are evolving from “n=1” treatments (a treatment effective for a single individual) into approaches that could transform care for many people living with rare conditions. Advances in genomic medicine are making it possible to design highly targeted treatments based on an individual’s genetic information. While these therapies may begin as bespoke solutions for a single patient, they can often be adapted, refined or reused to benefit others with similar conditions. While the research is evolving, the systems needed to deliver these treatments at scale are still catching up. From regulation to access, our guests discuss what needs to change to turn this potential into reality. Our host Sharon Jones, is joined by: Ana Lisa Tavares, Clinical Lead for Rare Disease Research at Genomics England Mel Dixon, Participant Panel member and CEO and Founder of Cure DHDDS If you enjoyed today’s conversation, please like and share wherever you listen to your podcasts. “However rare your condition is, someone has a right to have hope. Everybody should have a hope that we should be able to find a treatment.” You can download the transcript or read it below. Sharon: What if treatments once designed for just one person could now help many others? Thanks to advances in genomic medicine, regulations are changing and research is expanding. This opens up more options for treatments for rare conditions. But what does this mean and how close is real change? I'm Sharon Jones, and this is Behind the Genes. We look at how genomics is changing healthcare, covering everything from cutting-edge research to real-life stories. Individualised medicines are a fast-moving area, but there's still a big gap between scientific progress and what's actually happening to patients. You could call it the gap between hype and hope. Ana Lisa: However rare your condition is, someone has a right to have hope. Everybody should have a hope that we should be able to find a treatment. Sharon: Coming up, we'll hear from Ana Lisa Tavares, Clinical Lead for Rare Disease Research at Genomics England, and Consultant in Clinical Genetics at Cambridge University Hospital, as well as Mel Dixon, member of the Participant Panel at Genomics England and CEO and founder of Cure DHDDS. Mel opens this chat by explaining why developments in individualised healthcare really matter to her. Mel: This issue is really personal to me. I have three children, two of whom are affected with an ultra-rare DHDDS gene variant, for which there is currently no treatment. Their condition causes symptoms such as, well, it varies between mild to severe learning difficulties, seizures, tremors, and movement and coordination difficulties. But the, the most worrying thing for us was that this condition is actually also progressive. So over time it becomes more of a Parkinsonism and some patients experience dementia-like symptoms and psychosis. So for us to get a treatment that targets the genetic cause of, of their condition is, like, the most important thing in, in our lives. If we could intervene now, they could potentially, at the stage they're at, you know, live an independent life with, with some supports. But if the disease is left to progress, it would be a very different outcome for them. Sharon: I mean, that sounds so difficult and I can't even imagine how life is for you and your family. And I can see what is driving you to find anything to extend the life of your children and to give them that opportunity to, to have a better quality of life. And then Lisa. Ana Lisa: It's a huge burden for families to carry. And I think at the moment there's an additional layer of burden, which shouldn't fall on families, to feel like they need to forge a pathway for their child to have a chance of a treatment. That's, that's a lot to bear. Mel: I think as well, families feel they almost have to become mini scientists in their children's specific condition overnight, because you go to these appointments with the consultants and nobody's heard of the condition and they don't know, they just don't really know what to do with you. So they're asking you, you know, so tell me about this, this gene change. What, what does it do? What does it mean? So you have to become the mini professor in your child's condition to be able to advocate for them. We've had to really learn on our feet so that we're able to advocate and push for research into DHDDS, because without us doing it, nobody else was going to be. Sharon: Yeah. So that's, you know, that's partly what we're here and what this podcast is for, it's here to support families to, to understand this stuff. And Ana Lisa, can you just break it down to us, what is individualised medicines? Ana Lisa: An individualised medicine that's made for one individual person. In reality, sometimes there are other individuals that can also benefit from the same medicines, and sometimes actually, although the medicine is made for one specific person, it might be made using a strategy that other patients could also benefit from, either directly, exactly the same, even, or through tweaking them so that they could work for a different patient. In the context that they're most often referred to at the moment, they're therapies that are being made based on the genetic information about somebody. Sharon: Thank you. I mean, that sounds amazing. And now coming to you, Mel, what does receiving a diagnosis mean for a family? And how do you navigate the space between finally having answers and the reality that the treatment may not yet exist? Mel: So for us, I think, we went down the, the diagnostic route in the hope that we would be able to find a treatment for our children, or there would already be a treatment in place. But unfortunately when we got their diagnosis, we were told that their, their condition was ultra rare, neurodegenerative and also newly discovered. So there was, there was no treatment pathway and actually minimal research happening into it at the time. So it was frustrating, upsetting, um, and it felt like quite a hopeless situation at the start, but actually this was just over three years ago. And through a lot of proactiveness on our part in fundraising, we've been able to better understand the condition and we now have treatments in the pipeline. So in that three-year window, from there being nothing, we now have treatments both in terms of potential drug repurposing candidates and also, um, an individualised therapy called an ASO is also in development for them. So it was hard, but it's given huge benefit to us. Otherwise, we'd just be going, remaining going from specialist to specialist without having any answers or understanding why their symptoms were progressing. Sharon: I mean, that sounds really, really tough and you know, coming back to you, Ana Lisa, could you talk us through how genomics is changing the way we can treat rare conditions? You know, what types of individualised medicines now exist and how do they even work? Ana Lisa: Maybe I'll start with how some of these medicines are working. So with, without going into details, but the sort of principle that these medicines might be able to, to do something called gene editing. So our, our DNA, uh, the instruction manual is made up of genes and it's now can be possible scientifically to change even a single DNA letter code in somebody to try and ameliorate the symptoms of their rare condition. You know that's phenomenal scientific progress to be able to do that. I think a lot of people have heard about gene therapy, where one is trying to get into the body a gene or part of a gene that might be able to sort of replace the function of a gene that isn't working as it should. There are various other strategies. So our DNA is actually used to send messages to our body, if you like, to, to decode these instructions. And so there are medicines that target the next step in this process, the RNA, which are the ASO therapies that Mel was referring to earlier. And really what those are doing are either trying to correct for a protein in our body that isn't working as it should, or to try and get rid of one that shouldn't be there. And so they can act in different ways. And that's actually quite powerful, because you can, theoretically, use these strategies to correct for different genetic rare conditions. So I think going to the sort of first part of your question, maybe if I can phrase it as "directly at source". If you can go upstream and target in a very direct way the cause of a rare condition, then actually you might be able to apply those same principles to many different types of rare condition. We know that there are, you know, 8,000 as a very ballpark number of rare conditions, and it might be that these strategies could be used I don't want to say for all rare conditions, but for many rare conditions where we find the genetic cause, these strategies could collectively be a very powerful way to treat them. And traditionally we've had to understand all the underlying biology, find a druggable target, find a drug that could target that, that's safe, effective, et cetera. And that's a lot of work. And that's still very, very valuable. If we were going to do this for these thousands of conditions, it would probably take us hundreds to thousands of years, collectively. And these strategies provide a lot of hope for being able to do this in a, in a more efficient way, where we can actually use the information used to treat one rare condition and apply those learnings to another rare condition. Sharon : I mean, that's really helpful to understand. So if the science is there, why aren't more patients benefiting from it yet? You know, what's standing in the way from your perspective? Ana Lisa: That's a really good question, and it's complex because the, our whole ecosystem is made up of, of many parts that go from finding a potential strategy that could help a rare condition to a patient benefiting from that. And I think one thing that maybe we haven't touched on yet is the fact that rare conditions can be really rare and affect a really small number of people individually, even though we know collectively they affect so many. You know, in the past it's been easier, if you're taking a condition that's common, that affects thousands of people, it's easier to see and to be sure whether your new medicine is actually working as you think it does and should, and having the benefits that you think. The, the sort of regulators have really clear guidance. We have lots of knowledge about how to assess treatments and have a randomised clinical trial, for example. How the reimbursement process may work in a public healthcare system. And when you, when you, when you sort of set down into the really rare, this is difficult for each stage of the journey. The transformation that's needed is a whole, system-wide transformation to be able to regulate in a scalable, equitable way, these therapies that could actually be an N of one treatment for one individual, that actually maybe one day another individual may also benefit, and sometimes even a group of individuals. It's not just the, the regulator, it's also how do you make it viable. So again, you have to make it scalable, equitable. And even to implement in the NHS down to this very "N equals one" level, and demonstrate that patients could benefit from these treatments, might require sort of fancier ways of assessing these treatments, whether it's statistics, other methodology and I think it's really the system-wide nature that makes this tricky, but is also a fantastic opportunity for, for collaboration, because that, that sort of end goal and benefits could be so, so great. Sharon: Yeah, absolutely. And I mean, Mel, for your side of things, it must sound, you know, quite frustrating where the people in the rare community to not see the support being made more readily available? Mel: Yeah, it is particularly difficult for patients and their families. I think in our case, when you're dealing with a neurodegenerative condition, time is of the essence. So when you know that the science is available or it's ready, but you don't have the systems in place to implement them to the patients so that they can access these much-needed therapies, it's worrying and frustrating. And also I see our children are affected with, with, you know, one of these N of few conditions that there's, you know, there's only 59 confirmed cases of DHDDS worldwide, and we've seen how the system firsthand doesn't fit ultra-rare patients. We can't, when we were looking at drug repurposing, we can't do a traditional clinical trial because we don't have the patient numbers and we don't have the funding. So a placebo-controlled trial just wouldn't be possible for us when there's only, I think, seven confirmed patients in the UK and, um, four that we're actually in, in, in touch with. So it does feel, I think, as Ana Lisa was saying, that we really need a system rethink, um, and refit so that it does start to accommodate these ultra-rare conditions, especially now as there's therapies which are showing huge benefit to patients. Sharon: And so with like all of these challenges, where are you seeing things shift and what does meaningful progress really look like for you? Mel: At the end of last year, the MHRA announced that they were rewriting the regulatory framework for rare conditions, and that fills us with lots of hope for the future. They're recognising that the traditional systems don't work for particularly ultra-rare conditions, and now that we do have these therapies in the pipeline, we, we want to get the patients to be able to access them. And we're also seeing innovation in how evidence is generated and measured. We witnessed this firsthand with our son as he was undergoing baseline tests for his ASO therapy. You know, the use of digital biomarkers, of real-world evidence, how they're increasingly being used for these N of one or N of few populations. And how the individual receiving the treatment becomes their own comparator. So you're not relying on these big natural history studies of the disease or placebo controls. It's you're looking specifically at that individual, getting a really strong baseline and then looking, once they're dosed with the medication, is that improving or stabilising symptoms? So I think this shift in focus is really meaningful for the ultra-rare community and also for them to be part of the decision-making process of what, what benefits do they want from a drug? Like what is meaningful to them? I think there's much more talk about the patients and how the, what will benefit them most. It's not necessarily what the scientists would think or research would think would most benefit, but what, what would make a meaningful difference to the patient? Sharon: I mean, that's good to know because it's kind of putting the person at the centre of, you know, this is what it's all about, isn't it? It's not just the science. We're trying to treat people and it's putting people, people first. Ana Lisa: Just to build on that, it's exactly that, that awareness that is, is growing, I think, that there are so many people affected by a rare condition and, and however rare your condition is, someone has a right to have hope and that the system should be able to cater for many rare conditions, you know, whether they're an ultra-rare or an actually almost common rare condition, everybody should have a hope that we should be able to find a treatment. And it's not a hopeless situation that it's, you know, never going to happen or be too difficult. It's quite powerful, hope. If you can solve for the truly individualised medicine, then you at the same time may also be helping everyone in-between a really common condition and a really rare condition, because right now the system works for common conditions. And if you can take it right down to the sort of radical of, example of an individualised medicine made for one person, then you are also forcing the system to a change for everybody else. And I think that's one of the great benefits of thinking about it as a joined-up system. Sharon: So how do you each navigate between hype versus hope when it comes to rare therapies? Mel? Mel: I like to focus on hope, because when we got our diagnosis, we felt really hopeless and that's a really dark place for a family to be. But as we learnt more about their condition and the rare condition landscape and genomics, we actually learned of all these new therapies that were in the pipeline. We were hearing about, you know, recently, conditions like Huntington's Disease that you never, never previously had any disease-modifying treatment, how they're now being able to be treated with gene therapy with really positive effects. Similarly for other neurodegenerative conditions that have been treated with ASOs, how they're seeing not just disease stabilisation, but improvements. So I know it's, it's still, like, relatively early days with these technologies and therapies, but I think it, it allows families to have hope, which is, which is really, really important, because that statistic, you know, of the, of 95% of rare conditions not having a treatment, it's, it's a really brutal one, uh, to be told at the outset or to learn at the outset. So, you know, if, if these therapies can, can make a huge dent in that, that would be life-changing. It would make a profound difference to many, many families, and I think there's a lot of reason to have hope, taking all of that into consideration. Sharon: And then Lisa? Ana Lisa: I think to work in this area, one needs to be full of hope and optimism because there are so many, um, challenges to overcome as a community. Uh, but I think that means that people are also incredibly collaborative, because they know that we need to work together for this to succeed. And no one, you know, one individual, one organisation can do it on their own. It truly has to be a crosscutting, collaborative endeavour. The fact that we, in the UK, have resources like the National Healthcare System,Genomics England in partnership with the NHS runs a National Genomic Research Library. And so the fact that you could look at, at tens of thousands of, of genomes for many, many individuals with rare conditions. That gives me hope because it means that if a treatment is made for another person, it could be in a different country in the world, and if we could find another patient, it doesn't matter what specialty they're under, where they are, we should be able to find them and connect with their clinical team if, you know, if they've consented for the National Genomic Research Library. And so to me, that feels, that whilst there's, there is a lot of hype in the sense that some of the really well-publicised cases, really had a lot of people working on them and a lot of resources to make it happen. But that gives hope to everybody else that follows that actually it is doable and if we can make better systems, and having these national resources that we do, the fact that, there are a lot of guidelines being written at the moment, both international and national. And again, they show that the sort of scaffolding is starting to be in place to apply these in an equitable scalable way. It might not be that you're so much looking for a specific rare condition as for a particular type of genetic variant that could be targeted in the same strategic way, and that therefore you could look across many different rare conditions. So again, all these sort of pieces of the puzzle are, are filling me with, with, with hope. Sharon: You touched upon, um, inequity there. Now, you know, is there a risk of inequity given what we've talked about in terms of those challenges? Ana Lisa: I think we, we always have to have the lens of equity in everything we, we do. And that, and that really

In this explainer episode, we’ve asked Georgia Chan, Senior Data Wrangler at Genomics England, to explain what de-identified data is. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What do we mean by de-identified data? My name is Florence Cornish, and today I'm here with Georgia Chan. Georgia is Senior Data Wrangler here at Genomics England, which just means that she cleans up and adds structure to complicated data so that it becomes usable, and she is going to be telling us much more about the topic of de-identified data. Georgia, I think it would be a good place to start by talking about the National Genomic Research Library, which is the library that we at Genomics England store data in. So maybe you could explain more about that and what kind of data is in there. Georgia: Sure. Thanks Florence. So, we have genomic data. Genomic data is information that comes from a person's DNA. It helps us understand how the body works and why disease happens. This can include whole genome sequencing data, variants found in genes, small differences that make each of us unique, and information about how genes function or how they differ between people. Genomic data does not include a person's name or who they are. It's biological information, not identity, and it's used to understand health and disease. It's really important to note that by nature, it's nature, genomic information is incredibly rich. We all have millions of common genetic variants, but your whole genome is unique to you. So although genomic data alone can't directly identify you, it still counts as personal data under data protection. We also have clinical data. Clinical data provides real world context for the genomic data. It shows what's happening in someone's health. This can include diagnosis of a disease or a symptom, treatments that have been received, health outcomes over time, such as remission or progression, and this clinical data that help researchers see how genetic differences relate to symptoms, treatment response, and long-term outcomes. So, we have both of these kinds of data. Genomic data on its own can be hard to interpret, and clinical data on its own only tells part of the story. Together, they allow researchers to better understand how diseases develop, helps them discover new or more targeted treatments, and it helps them improve diagnosis, care, and outcomes. And this is why both types of this data are used together in the National Genomic Research Library. Florence: And so, both of these data types, both clinical and genomic, we say that they are de-identified. But what exactly does that mean? Georgia: Yes, good question. De-identified data means that information which directly identifies a person has been changed or removed from a health record before researchers can access it. And in practice, it means that researchers cannot see who the person is. The data cannot be used to contact individuals, and a person's identity is protected by design, which means that necessary safeguards are embedded into every stage of a service or process. So, researchers work with the data, but not with people's identities. Florence: Could you tell me a little bit more about why it's so important to de-identify data in this way? Georgia: Sure. De-identification creates a safe middle ground. It means that data can be used to improve healthcare whilst people's privacy and trust is respected. So, without de-identification, every new research question would require individual contact and large-scale, long-term research would be extremely difficult. With de-identification, we reduce the risk of someone being identified. We prevent inappropriate use of data, and we ensure that data is used only for approved research. And it's important to note also that it sits alongside a list of other safeguards, so that helps ensure data is used responsibly, such as secure Research Environment, strict access control, independent ethical and governance approvals. And all of those safeguards are provided in Genomics England's Research Environment. Florence: I think a common question that people might have, or a question that I definitely had when I first heard the term, is how de-identified data is different from anonymous data. Georgia: Yes, it is a good question. So, anonymised data cannot be linked back to an individual and is no longer considered personal data, whereas de-identified anonymised data, it has identified as hidden from researchers, but it can still be relinked by a trusted authorised organisation if needed. So, in healthcare research, de-identification is often preferred because it allows long-term follow up. It also allows updates as new health information becomes available, and also allows corrections or withdrawals when they occur and when they're appropriate. Florence: So say a researcher did find something in the data that they might want to feedback, how can we re-identify that participant? What does that process look like? Georgia: Researchers cannot re-identify participants themselves. At Genomics England, if researchers do make a new discovery that could help an individual, for example, a possible diagnosis for a rare condition, we have an in-house clinical team who can link back to that individual's details and work with their NHS clinicians to establish if this new insight can be fed back. So if something clinically important is discovered, research is reported through a formal governance process, and then a trusted authorized team, not the researchers who re-identify the participant, and this ensures that researchers never know who the participant is and individuals remain protected. Whilst important findings can still benefit patients, and this would only happen when it's ethically approved and clinically appropriate. Florence: Great. Well, I think we'll finish there. Thank you so much, Georgia, for taking the time to talk us through the meaning of de-identified data and why it is so important to protect participants. Georgia: Thank you, Flo. And let's remember that de-identified data isn't about hiding information. It's about using it responsibly. Florence: Absolutely. If you want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

Blood cancers are the fifth most common group of cancers in the UK. But for a small number of people, the condition may have an inherited genetic cause. In this episode of Behind the Genes, we explore the role of genetics in blood cancer, and what an inherited risk means for patients and their families. Our guests explain what blood cancer is, how inherited factors can increase risk, and why multidisciplinary teamwork is key to supporting families. They also look ahead to future advances, from whole genome sequencing to prevention trials. Our host Amanda Pichini, Clinical Director at Genomics England, is joined by: Dr Katie Snape, Principal Clinician at Genomics England and Consultant Cancer Geneticist Bev Speight, Principal Genetic Counsellor Dr Sarah Westbury, Consultant Haematologist “By doing whole genome sequencing we get all of the information about all of the changes that might have happened, we know whether any are inherited, but importantly, we’re certain of the ones that have just occurred in the cancer cells and can help guide us with their treatment.” You can download the transcript or read it below. Amanda: Hello, and welcome to Behind the Genes. Sarah: When we think about blood cancers, it’s a whole range of different conditions and when you talk to patients who are affected with blood cancers or are living with them, their experiences are often really different from one another, depending in part on what kind of blood cancer they have. We also know that blood cancers affect not just the cell numbers but also the way that those cells function, and so the range of symptoms that people can get is really variable. Amanda: I am your host, Amanda Pichini, clinical director at Genomics England and genetic counsellor. Today I’ll be joined by Dr Katie Snape, principal clinician at Genomics England and a consultant cancer geneticist in London, Bev Speight, a principal genetic counsellor in Cambridge, and Dr Sarah Westbury, and haematologist from Bristol. They’ll be talking about blood cancers and the inherited factors that increase blood cancer risk. If you enjoy this episode, we’d love your support, so please subscribe, rate and share on your favourite podcast app. Let’s get started. Thanks to everyone for joining us today on this podcast, we’re delighted to have so many experts in the room to talk to us about blood cancer. I’d love to start with each of you introducing yourself and telling us and the listeners a little bit about your role, so, Sarah, could we start with you? Sarah: Sure. It’s great to be here. My name’s Sarah Westbury, and I’m a consultant haematologist who works down in Bristol. And my interest in this area is I’m a diagnostic haematologist so I work in the laboratories here in the hospitals, helping to make a diagnosis of blood cancer for people who are affected with these conditions. And I also look after patients in clinic who have different forms of blood cancer, but particularly looking after families who have an inherited predisposition to developing blood cancer. And in the other half of my job, I work as a researcher at the University of Bristol. And in that part of my job, I’m interested in understanding the genetic basis of how blood counts are controlled and some of the factors that lead to loss of control of those normal blood counts and how the bone marrow functions and works. Amanda: Thank you. That’s really interesting, we’ll be looking forward to hearing more about your experience. Bev, we’ll come to you next. Bev: Thank you. Hello everyone, I’m Bev Speight, I’m a genetic counsellor, and I work at Addenbrooke’s Hospital in Cambridge. I work with families with hereditary cancers in the clinical genetic service, and for the last six years or so have been focused on hereditary blood cancers. So we’ve been helping our haematologists across the region to do genetic tests and interpret the results, and then in my clinic seeing some of the onward referrals that come to clinical genetics after a hereditary cause for blood cancer is found. I’m also part of the Council for the UK Cancer Genetics Group. Amanda: Thank you, Bev. And Katie, over to you. Katie: Hello, I’m Katie Snape. I’m a genetics doctor and I am a specialist in inherited cancer. So we look after anyone who might have an increased chance of developing cancer in their lifetime due to genetic factors. I am the chair of the UK Cancer Genetics Group, so that’s a national organisation to try and improve the quality of care and care pathways for people with inherited cancer risk in the UK. And I have a special interest in inherited blood cancers through my work at King’s College Hospital, I work in the haematology medicine service there seeing individuals who might have or have been diagnosed as having an inherited component to their blood cancers. So it’s great to be here. Amanda: Excellent, thank you for those introductions. I’d like to then dive right in and understand a little bit more about blood cancers. So, Sarah, could you tell us a little bit more about what blood cancer is? Sarah: Yes, sure. The term blood cancer is used to describe a whole range of different kinds of cancer, all of which affect some part of the blood or sometimes parts of the immune system that kind of gets represented as part of the blood. So it’s really describing a big group of conditions rather than one single kind of condition or entity itself. But like any form of cancer, we understand blood cancers as being conditions where because cells as part of the blood system are rapidly dividing and normally doing so under really well controlled circumstances to produce just the right balance of blood cells and just the right number of those cells. In a cancer affecting those cells, we see that that loss of control results in either too many of one type of blood cell being produced or too few, or that balance being lost. And like any form of cancer, this is because of genetic changes that happen in individual cells that then go on to grow in a way that is not controlled and well regulated. And because when we talk about blood cancer we’re talking about such a wide range of different kinds of cancer affecting different cells within that blood system, there’s a really wide range of different conditions. From conditions that we might think of as being like a form of acute leukaemia, so something that produces often symptoms and signs in patients very quickly and they can often feel quite unwell quite soon and then get picked up with having this condition because they present feeling unwell. All the way to chronic and slow growing cancers that can be found completely by chance and serendipity when blood tests are done for other reasons. So when we think about blood cancers, it’s a whole range of different conditions. And when you talk to patients who are affected with blood cancers or are living with them, their experiences are often really different from one another, depending in part on what kind of blood cancer they have. We also know that blood cancers affect not just the cell numbers, but also the way that those cells function. And so the range of symptoms that people can get is really variable, again depending on which of the blood cells are really affected by that. And it may be that during the course of some of the conversations we have today in this podcast, we’ll perhaps focus on particular kinds of blood cancer. But like any cancer, it’s that disruption of the normal growth and development of cells that means that the number and function of those blood cells has been disrupted in some way. Amanda: Thank you so much for explaining that, Sarah, that’s really helpful. In terms of across the range of blood cancers, is that something that people can get at any age, and how common is it? Sarah: It does depend, as we were sort of talking about that really wide range of different disorders that make up that group of blood cancers. And individually each of those blood cancers is reasonably uncommon compared to cancers that we might typically think of, like breast cancer or colon cancer. But actually, if you group blood cancers together, they make up quite a sizeable proportion, and they’re actually as a group the fifth most common form of cancer that’s diagnosed in people in the UK. In adults in particular we think that perhaps people diagnosed with leukaemia would make up about 3% of the new diagnosis of cancer made in any year. Amanda: So coming to you, Bev, when we talk about inherited blood cancers, what are the differences between those and blood cancers more generally? Bev: So at point of diagnosis, it may not be obvious that somebody with a new blood cancer diagnosis is one of the minority of people in that big group as Sarah has described, who has an inherited cause. So it may not be immediately obvious. However, in the last few years certainly, it’s become more and more routine to do quite broad genetic testing. Often on a bone marrow sample or blood, because that is done looking for genetic changes, which are part of all cancer and we find within cancer cells, that can help with treatment planning. It can also find that there is an inherited cause to that new blood cancer diagnosis. Sometimes that might not be clear cut, sometimes that might be inferred from the genetic tests that are done on the blood or the bone marrow. And the proportion of blood cancers in that huge group which do have an inherited cause is fairly small, the actual proportion will depend a bit on the age of the patient and the specific subtype of blood cancer. Amanda: Okay, and could you talk us through how some of those inherited genetic factors can increase the chance of a person developing blood cancer, how does that work? Bev: Yes, so if we know that there is an inherited cause for blood cancer, then what we mean by that most of the time is that a change in a single gene has been found. And that there is enough research evidence and enough known about that specific change in that gene to say to the person who’s been diagnosed, there is at least in part or perhaps a full explanation for why that blood cancer has developed and this could be shared in the family. So at that point it’s information that not only has implications for the person in treatment, but also their relatives. Depending on what sort of gene alteration it is and which gene it’s found in, there are different inheritance patterns, and that changes the sorts of information that we give about risks for relatives. So for lots of the genetic tests that detect an inherited cause in adults when they’re diagnosed, that’s most often what we would call an autosomal dominant inheritance pattern. Essentially that means you only need to have one gene alteration which is in that person’s normal non-cancerous DNA inherited from a parent and can be passed onto a child. And for people in the family who have inherited this one genetic change, then they are likely to be at increased risk of developing blood cancer. Sometimes with particularly the children’s blood cancers, if an inherited cause is found, it can be a different pattern, which we call autosomal recessive. And that’s where two gene changes are found and one has been inherited from each parent. So parents might be what we call carriers and have one each just by chance, both have been passed onto a child who has developed blood cancer either in childhood or possibly later on, and that’s the pattern we call autosomal recessive. There are other inheritance patterns too. The third one that we come across being X-linked, and so that has a gender component. That’s where there’s a change on the X chromosome, women have two X’s, and men have one X and one Y. So sometimes with the X-linked conditions we’re more likely to see the clinical signs of a condition in boys and men because they’ve only got that one X chromosome. But those are less common in the context of talking about hereditary blood cancers. Amanda: Thank you. That’s really helpful to understand. So it sounds like you're saying that these forms of blood cancers that are caused by a single gene are relatively rare. And also by having one of these changes, it’s not a given that that person will develop a blood cancer, but it makes them more likely, and how likely that is might depend on the inheritance pattern or the type of condition. Bev: That’s right. So what we’re saying is it can give either part of full explanation for the blood cancer diagnosis, and it could confer a risk to family members, but that doesn’t mean they definitely will develop it. We’re talking about an increased risk compared to the population risk. Amanda: Right. I can imagine for those families to some extent it might be helpful to know the underlying reason why they had that blood cancer, but again, that’s just a small proportion. So, Katie, could I come to you next? What about the rest of all the blood cancers, how do they occur? Katie: Yes, thanks, Amanda. So most blood cancers will occur just by chance. We also know that there are some environmental factors that can increase the risk of blood cancers, so, for example, serious radiation exposure, something like that. What Bev has described is where there is this sort of quite rare condition where there is a kind of single gene that’s really important for the blood cells in terms of keeping those control mechanisms that Sarah described. And that’s not working properly, which has increased the risk of a blood cancer. But we also sometimes see some families where there is more blood cancer, or the same type of blood cancer in that family than we might expect by chance. We think that’s probably not due to a single high risk genetic factor, but might be due to kind of multiple lower risk genetic factors that are sort of shared by close family members and can add up together to increase the risk a little bit. And we call that familial risk or polygenic risk. We don’t have a test for that at the moment. We wouldn’t offer usually any extra screening or testing to those families, but we would just suggest obviously family members are aware of any signs of symptoms of blood cancers and seek any advice if they’re concerned. But, you know, the majority of blood cancers are not due to genetic factors, and it’s sort of environmental or chance or bad luck. Amanda: Okay, so it’s clear that obviously blood cancer is almost an oversimplification, within that category there’s so many different types, so many ways that it could happen in a person. So, Bev, if we’re dealing with that type of blood cancer that is inherited or has some heritability, can you tell us more about what that means for the family? What kind of impacts do you see that having for them? Bev: Yes, of course. So clearly this is another layer of information that’s often coming at a family during a time where somebody is often recently diagnosed with blood cancer of one sort or another and is having to take in a lot of information about treatment and all of the uncertainty and anxiety that goes with that. So for this minority of patients and families where there is new information about an inherited cause, that needs conveying in a timely but sensitive way, bearing in mind what else is happening. And for some people it can come as a major shock and really an additional burden at that time. I think the reaction to that will of course depend on lots of factors. And what we also see is that this question about a new cancer diagnosis of any sort, including blood cancers, can generate the question in people’s mind, particularly if they’ve got children, about does this change the risk for relatives? So sometimes this new information that, actually, there is an inherited cause is an answer to a question that families have already got. And that might be because of what Katie’s described as familial clustering, there might already have been this known history in the family. So sometimes this information can feed into that and actually be quite a helpful answer. But it’s quite normal for families to feel quite mixed about this and for different family members to have a different approach to it. When there’s the offer of what we would call predictive testing, if we found a change in a single gene in somebody with blood cancer which we’re saying is a hereditary cause for that, that might open the door for relatives to access predictive testing. I.e., the opportunity to discuss and possibly take up a genetic test for themselves when they haven't had cancer themselves, but there’s an opportunity to try and quantify whether or not they’re at increased risk. We know in families the uptake of those kinds of tests is different, and a lot of it is to do with timing and the way people respond to this in families might depend on their response to the cancer diagnosis in their relative, and of course what else is going on in their life at the time. This aspect for the family is where clinical genetic services come in, because these initial tests in the person with blood cancer are done in their haematology/oncology setting, and normally the results about an inherited cause has been found are conveyed through that service. That’s when a referral to clinical genetics happens. And in our specialist service we’re addressing those additional concerns for the family which arise because of this diagnosis. Amanda: Thanks, Bev, for explaining that. Sarah, coming back to you. Could you tell me then if someone has an inherited blood cancer does it also change the way that the patient is treated? Sarah: Well, it certainly can do, and again, it does depend a little bit on the specific circumstances of that particular person and the form of inherited blood cancer predisposition that they have. But certainly if we think about treatment as a whole, then for a lot of people it does affect the way that we might recommend treatments or look after them and their families. So, for example, for some patients who have a diagnosis of an inherited form of blood cancer, we know that some treatments might be more or less effective for their particular set of circumstances. And so that can sometimes influence the specific treatment recommendations that we would make, particularly thinking about, for example, the risks that the cancer might come back again after it’s been treated. Or thinking about whether or not some of the typical drug regimes that might be used might be perhaps more likely to cause them side effects or problems with tolerating that treatment. So it can certainly make some changes in that respect. For some people, to be fair a minority of people with blood cancers, they may need a stem cell transplant as part of their treatment to hopefully cure them of their blood cancer. And this as I say is a treatment that’s required for a minority of patients as a whole who have a diagnosis of a blood cancer. But for those people who have got an inherited predisposition and who might be recommended a stem cell transplant as part of their treatment, then knowing about a familial risk for this condition can also be really important. For making sure that if a family member is being considered as a donor for example that we’re being really careful to make sure that we’re not choosing a donor that might also be affected by the same underlying blood cancer predisposition. Because this can obviously cause problems for the person that’s receiving the stem cells if it turns out that the person they’re receiving them from actually has the same inherited condition as them. So in that respect knowing about the underlying predisposition and genetic cause for their cancer can be helpful. But in a more sort of general sense, yes, the other thing that it can have a big difference for is that some of these inherited cancer predispositions and syndromes also have other health conditions associated with them. So it might be that that genetic diagnosis predisposes somebody not only to a form of blo

In this explainer episode, we’ve asked Réka Novotta, Research Ethics Operations Manager at Genomics England, to explain what informed consent is. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What do we mean by informed consent? My name is Florence Cornish, and today I'm here with Réka, who is Research Ethics Operations Manager here at Genomics England, and she's going to be telling us much more about it. I think it would first be helpful Réka, if you could explain the word consent. Réka: The broad definition of consent is that it's the voluntary agreement given by an individual to participate in a particular activity. We all probably give consent to a lot of different things each day without really realizing it. So, you go on to read the news in the morning, and the website asks for your consent to process cookies. You maybe go to a routine GP appointment later, and you stick your arm out for them to measure your blood pressure. Maybe you even go to a podcast and you give consent to a host to record your voice. So, these are all based on affirmative action made by you while taking into consideration the information that's available to you. The technical definition of consent often includes that it's freely given, meaning that you are not coerced. That it’s specific, meaning when you stick your arm out for your doctor, you're only agreeing to that part of the examination, and perhaps most importantly, that person needs to be adequately informed for the consent to be meaningful. Florence: So you gave lots of really interesting examples there. I think it would be good to understand what we mean by informed consent and where this distinction comes in. How does it differ? Réka: By informed consent, we mean that the person consenting has been provided with all relevant and necessary information about the activity, in a format that is accessible and understandable for them. And that latter part of the sentence is really important, because if you go to the doctor and the doctor speaks to you in French, if you speak French, then wonderful, you have all the information that you need. But if you don't, even though the information is technically there, you not understanding it makes it impossible for your consent to be informed. Similarly, if you think about maybe an older person who's not familiar with technology, if they see a QR code, they might not necessarily know what to do with it, even if it would technically lead to all of the information that they would ever want to know about Genomics England. Florence: So you mentioned Genomics England, obviously we both work for Genomics England, this is a Genomics 101 podcast. So what do we mean by informed consent in the context of genomics? Where does it come into play? Réka: So if we think about informed in a traditional research study, they test a drug, the treatment either works or it doesn't work, and there's analysis of that data, and that's sort of the end of the process. With genomics, there's a huge amount of information that gets generated and analysed, and the field itself is rapidly evolving. So we may not have an answer today, but we might do tomorrow, which puts our participants' data in the research resource that we manage in a really unique position. Because of that, it's even more important perhaps for this consent to be ongoing. Consent is often incorrectly considered a tick box exercise, where you receive information, you consider the information, you make a decision, and that's sort of it. Whereas for genomics, it's important that it is an ongoing conversation and it doesn't just stop at the signing of a form. We also employ what's called a broad consent model. Genomics England manages the National Genomic Research Library, which rather than being a single study, is a resource for a wide range of research uses. It allows us to gain permission via the informed consent conversations for the storage and the use of data and samples for upcoming studies that we don't yet know about. And this eliminates the need to reconsent each participant every time a researcher starts to use their data for a new research project, and in turn, and this also feeds back to the need for ongoing conversation, a fully informed consent is very hard to achieve at the time of consenting. Florence: So you mentioned the National Genomic Research Library, and we actually did a previous explainer podcast episode about this. So, if listeners would like to learn more about it, you can check out our previous Genomics 101 episode: What is the National Genomic Research Library? Réka, I'd be interested to know, are there any challenges related to informed consent that are specific to the field of genomics? Réka: Yeah, so there’s many fascinating challenges. There's one that I really want to highlight, which is the family aspect. It's a lot more pronounced in genomics than it is in traditional medicine. The information that you receive, it doesn't only affect you, but it also affects your parents, your siblings, your existing, or even your future children, which is quite unique, and there's a challenge in how we articulate that without causing further anxiety. Florence: So speaking of the challenges there, the family aspect and the fact that genomics as a field is rapidly evolving, I think this highlights how important it is that we embed informed consent into our practices. Could you tell me a bit about how we're doing this at Genomics England? Réka: We follow best practice in informed consent called information layering, where we provide materials for our research in different formats. And this can ensure that participants can get the depth of understanding that they need, without feeling overwhelmed by a massive amount of information from the outset. So this includes longer and shorter information sheets, providing materials and training for healthcare professionals so that they can have conversations with potential participants. We also have lots of different copy on our website. We have videos, and this podcast as well. And it's all part of what we call patient and public involvement and engagement or PPIE, which means that we co-produce our materials involving members of the public and patients in the design of our materials, making sure that they present accessible and understandable information. It is really important for us not to, as you say, mark our own homework. What makes sense to one person might not make sense to another, and it's important to get lots of different perspectives. And I just wanted to shout out the Participant Panel who's a committee of wonderful people who help us, and also keep us accountable in everything that we do. Florence: What would happen if say, somebody gave informed consent for their data to be stored in the National Genomic Research Library, but then they change their mind and they want to take it back? What would happen then? Réka: So we offer 2 types of withdraw from a resource. There is an option to withdraw partially or to unsubscribe, which means that you can leave your de-identified donated data for researchers to analyse, but not receive any updates or contact from us going forward. You can also decide to withdraw your participation fully, and that's where we make your data unavailable for future research. One of the key pillars in informed consent and the consent model that Genomics England employs, is that research participants can withdraw their consent to participate at any time without giving us a reason. So, it doesn't matter if you submit your request on a website or on a paper form or if you call us, we will respect your decision with no questions asked. Florence: Thank you so much for coming on and for walking us through the meaning of informed consent, and why it's so important in the context of healthcare and research. If you want to learn more about terms we use in genomics, check out our other podcasts at www.genomicsengland.co.uk, or, wherever you get your podcasts. Thank you for listening.

In this special episode, recorded live at the 2025 Genomics England Research Summit, host Adam Clatworthy is joined by parents, clinicians and researchers to explore the long, uncertain and often emotional journey to a genetic diagnosis. Together, they go behind the science to share what it means to live with uncertainty, how results like variants of uncertain significance (VUS) are experienced by families, and why communication and support matter just as much as genomic testing and research. The panel discuss the challenges families face when a diagnosis remains out of reach, the role of research in refining and revisiting results over time, and how collaboration between researchers, clinicians and participants could help shorten diagnostic journeys in the future. Joining Adam Clatworthy, Vice-Chair for the Participant Panel, on this episode are: Emma Baple – Clinical geneticist and Medical Director, South West Genomic Laboratory Hub Jamie Ellingford – Lead genomic data scientist, Genomics England Jo Wright – Member of the Participant Panel and Parent Representative for SWAN UK Lisa Beaton - Member of the Participant Panel and Parent Representative for SWAN UK Linked below are the episodes mentioned in the episode: What is the diagnostic odyssey? What is a Variant of Uncertain Significance? Visit the Genomics England Research Summit website , to get your ticket to this years event. You can download the transcript , or read it below. Sharon: Hello, and welcome to Behind the Genes. My name is Sharon Jones and today we’re bringing you a special episode recorded live from our Research Summit held in June this year. The episode features a panel conversation hosted by Adam Clatworthy, Vice-Chair of the Participant Panel. Our guests explore navigating the diagnostic odyssey, the often-complex journey to reaching a genetic diagnosis. If you’d like to know more about what the diagnostic odyssey is, check our bitesize explainer episode, ‘What is the Diagnostic Odyssey?’ linked in the episode description. In today’s episode you may hear our guests refer to ‘VUS’ which stands for a variant of uncertain significance. This is when a genetic variant is identified, but its precise impact is not yet known. You can learn more about these in another one of our explainer episodes, “What is a Variant of Uncertain Significance?” And now over to Adam. -- Adam: Welcome, everyone, thanks for joining this session. I’m always really humbled by the lived experiences and the journeys behind the stories that we talk about at these conferences, so I’m really delighted to be hosting this panel session. It’s taking us behind the science, it’s really focusing on the people behind the data and the lived experiences of all the individuals and the families who are really navigating this system, trying to find answers and really aiming to get a diagnosis – that has to be the end goal. We know it’s not the silver bullet, but it has to be the goal so that everyone can get that diagnosis and get that clarity and what this means for their medical care moving forwards. So, today we’re really going to aim to demystify what this diagnostic odyssey is, challenging the way researchers and clinicians often discuss long diagnostic journeys, and we’ll really talk about the vital importance of research in improving diagnoses, discussing the challenges that limit the impact of emerging research for families on this odyssey and the opportunities for progress. So, we’ve got an amazing panel here. Rather than me trying to introduce you, I think it’s great if you could just introduce yourselves, and Lisa, I’ll start with you. Lisa: Hi, I’m Lisa Beaton and I am the parent of a child with an unknown, thought to be neuromuscular, disease. I joined the patient Participant Panel 2 years ago now and I’m also a Parent Representative for SWAN UK, which stands of Syndromes Without A Name. I have 4 children who have all come with unique and wonderful bits and pieces, but it’s our daughter who’s the most complicated. Adam: Thank you. Over to you, Jo. Jo: Hi, I’m Jo Wright, I am the parent of a child with an undiagnosed genetic condition. So I’ve got an 11-year-old daughter. 100,000 Genomes gave us a VUS, which we’re still trying to find the research for and sort of what I’ll talk about in a bit. And I’ve also got a younger daughter. I joined the Participant Panel just back in December. I’m also a Parent Rep for SWAN UK, so Lisa and I have known each other for quite a while through that. Adam: Thank you, Jo. And, Jamie, you’re going to be covering both the research and the clinician side and you kind of wear 2 hats, so, yeah, over to you. Jamie: Hi, everyone, so I’m Jamie Ellingford and, as Adam alluded to, I’m fortunate and I get to wear 2 hats. So, one of those hats is that I’m Lead Genomic Data Scientist for Rare Disease at Genomics England and so work as part of a really talented team of scientists and engineers to help develop our bioinformatic pipelines, so computational processes. I work as part of a team of scientists and software engineers to develop the computation pipelines that we apply at Genomics England as part of the National Health Service, so the Genomic Medicine Service that families get referred to and recruited to, and we try to develop and improve those. So that’s one of my hats. And the second of those is I am a researcher, I’m an academic at the University of Manchester, and there I work really closely with some of the clinical teams in the North West to try and understand a little bit more about the functional impact of genomic variants on kind of how things happen in a cell. So, we can explore a little bit more about that but essentially, it’s to provide a little bit more colour as to the impact that that genomic variant is having. Adam: Great, thank you, Jamie. Over to you, Emma. Emma: My name’s Emma Baple, I’m an academic clinical geneticist in Exeter but I’m also the Medical Director of the South West genomic laboratory hub, so that’s the Exeter and Bristol Genomics Laboratory. And I wear several other hats, including helping NHS England as the National Specialty Advisor for Genomics. Adam: Thank you all for being here. I think it’s really important before we get into the questions just to ground ourselves in like those lived experiences that yourself and Jo and going through. So, Lisa, I’m going to start with you. The term ‘diagnostic odyssey’ gets bandied around a lot, we hear about it so many times, but how does that reflect your experience that you’ve been through and what would you like researchers and clinicians to understand about this journey that you’re on, essentially? Lisa: So I think ours is less an odyssey and more of a roller-coaster, and I say that because we sort of first started on a genetic journey, as it were, when my daughter was 9 weeks of age and she’s now 16½ – the half’s very important – and we still have no answers. And we’ve sort of come a bit backwards to this because when she was 6 months old Great Ormond Street Hospital felt very strongly that they knew exactly what was wrong with her and it was just a case of kind of confirmation by genetics. And then they sent off for a lot of different myasthenia panel genes, all of which came back negative, and so having been told, “Yes, it’s definitely a myasthenia, we just need to know which one it is,” at 4 years of age that was removed and it was all of a sudden like, “Yeah, thanks, sorry.” And that was really hard actually because we felt we’d had somewhere to hang our hat and a cohort of people with very similar issues with their children, and then all of a sudden we were told, “No, no, that’s not where you belong” and that was a really isolating experience. I can remember sort of saying to the neuromuscular team, “Well is it still neuromuscular in that case?” and there was a lot of shrugging of shoulders, and it just… We felt like not only had we only just got on board the life raft, then we’d been chucked out, and we didn’t even have a floaty. And in many ways I think I have made peace with the fact that we don’t have a genetic diagnosis for our daughter but it doesn’t get easier in that she has her own questions and my older children – one getting married in August who’s already sort of said to me, you know, “Does this have implications for when we have children?” And those are all questions I can’t answer so that’s really hard. Adam: Thank you, Lisa. Yourself, Jo, how would you describe the odyssey that you’re currently experiencing? Jo: So my daughter was about one when I started really noticing that she was having regressions. They were kind of there beforehand but, I really noticed them when she was one, and that’s when I went to the GP and then got referred to the paediatrician. So initially we had genetic tests for things like Rett syndrome and Angelman syndrome, which they were all negative, and then we got referred on to the tertiary hospital and then went into 100,000 Genomes. So we enrolled in 100,000 Genomes at the beginning of 2017, and we got our results in April of 2020, so obviously that was quite a fraught time. Getting our results was probably not as you would want to do it because it was kind of over the phone and then a random letter. So, what I was told in that letter was that a variant of uncertain significance had been identified and they wanted to do further research to see if it might be more significant. So we were to be enrolled into another research project called Splicing and Disease, which wasn’t active at the time because everything had been put on hold for COVID, but eventually we went into that. So, I didn’t know what the gene was at that point, when I eventually got the form for going to get her bloods done… So that went off and then that came back and the geneticist said, “That gives us some indication that it is significant.” So, since that point it’s been trying to find more information and research to be able to make it a diagnosis. There have been 2 sort of key things that have happened towards that but we’re still not there. So one of the things is that a research paper came out earlier this year so that’s kind of a little bit more evidence, it’s not going to give us a diagnosis but it kind of, you know, sits there. And the other thing is that my geneticist said, “Actually, yeah, it looks like it’s an important change.” That’s as far as we’ve got. So we’ve still got work to do to make it a diagnosis or not. Obviously if it is a diagnosis, it is still a one-of-a-kind diagnosis, so it doesn’t give me a group to join or that kind of thing. But now I’ve got that research paper that I’ve read and read, and asked ChatGPT to verify that I’ve understood it right in some places, you know, with the faith that we put into ChatGPT (laughs), I’ve got a better understanding and I’ve got something now that I can look back on, the things that happened when my daughter was one, 2, 3, 4 and her development was all over the place and people thought that I was slightly crazy for the things I was saying, that “Actually, no, I can see what’s happening.” So, it’s like the picture’s starting to come into focus but there’s work to do. I haven’t got a timeframe on that, I don’t know when it’s going to come together. And I always say that I’m a prolific stalker of the postman; ever since our first genetic tests you’re just constantly waiting for the letters to drop through the door. So a diagnostic odyssey to me is just waiting for random events. Adam: I think what you’ve both kind of really clearly elaborated on is how you’re the ones that are having to navigate this journey, you’re the ones that are trying to piece this puzzle together, and the amount of time you’re investing, all whilst navigating and looking after your child and trying to cope with the daily lived experience as well. And something you’ve both touched on that I’d love to draw out more is about how exactly was the information shared with you about the lack of diagnosis or the VUS or what’s going on, because in our case you get this bit of paper through the post that has all these numbers and it’s written in clinical speak and we had no conversation with the geneticist or the doctors. You see this bit of paper and you’re reading it, scared for what the future will hold for your child, but I’d love to know like how were you communicated whilst all this is going on, how did you actually find out the next steps or any kind of future guidance. Lisa: So I think in our case we kept sort of going onto neuromuscular appointments, and I think for probably the first 5 years of my daughter’s life I kind of had this very naïve thought that every time we turned up to an appointment it would be ‘the one’ and then… I think it would’ve been really helpful actually in those initial stages if they had said to us, “Actually, we don’t know when this is going to happen, if it’s even going to happen, you need to kind of prepare yourself for that.” It sounds fairly obvious to say but you don’t know what you don’t know. And in some ways we were getting genetic test results back for some really quite horrible things and they would tell us, “Oh it’s good news, this mitochondrial disorder hasn’t come up,” and so part of you is like, “Yay!” but then another part of you is thinking, “Well if it’s not that what is it?” And we’ve very much kind of danced around and still don’t really have an answer to whether it’s life-limiting. We know it’s potentially life-threatening and we have certain protocols, but even that is tricky. We live in North Yorkshire, and our local hospital are amazing. Every time we go in, if it’s anything gastro-related, they say to me, “What’s the protocol from Great Ormond Street?” and I say, “We don’t have one” (laughs) and that always causes some fun. We try to stay out of hospitals as much as we absolutely can and do what we can at home but, equally, there’s a point where, you know, we have to be guided by where we’re going with her, with the path, and lots of phone calls backwards and forwards, and then is it going to be a transfer down to Great Ormond Street to manage it. And actually the way I found out that nothing had been found from 100,000 Genomes was in a passing conversation when we had been transferred down to Great Ormond Street and we’d been an inpatient for about 6 weeks and the geneticist said to me, “So obviously with you not having a diagnosis from the 100,000 Genomes…” and I said, “Sorry? Sorry, what was that? You’ve had the information back?” And she said, “Well, yes, did nobody write to you?” and I said, “No, and clearly by my shock and surprise.” And she was a bit taken aback by that, but it happened yet again 2 years later (laughs) when she said, “Well you know everything’s been reanalysed” and I said, “No.” (Laughs) And, so that’s very much, it still feels an awful lot like I’m doing the heavy lifting because we’re under lots of different teams and even when they’re working at the same hospital they don’t talk to each other. And I do understand that they’re specialists within their own right, but nobody is really looking at my daughter holistically, and there are things that kind of interrelate across. And at one of the talks I attended this morning they were talking about the importance of quality of life, and I think that is something that has to be so much more focused on because it’s hard enough living without a diagnosis, but when you’re living with a bunch of symptoms that, I think the best way I can describe it is at the moment we’ve got the spokes of the umbrella but we don’t have the wrapper, and we don’t know where we’re going with it. We can’t answer her questions, we can’t even necessarily know that we’re using the most effective treatments and therapies for her, and she’s frustrated by that now, being 16, in her own right, as well as we are. And I’m panicking about the navigation towards Adult Services as well because at the minute at least we have a clinical lead in our amazing local paediatrician but of course once we hit and move into that we won’t even have him and that’s a really scary place to be, I think. Adam: Jo, is there anything you wanted to add on that in terms of how you’ve been communicated to whilst all this is going on? Jo: Yeah, so I think part of what makes it difficult is if you’re across different hospitals because they’re not necessarily going to see the same information. So obviously it was a bit of a different time when I got our results, but I got our results on a virtual appointment with a neurologist in one hospital, in the tertiary hospital, and because he could see the screen because it was the same hospital as genetics, and he said, “Oh you’ve got this” and then the letter came through later. When I had my next appointment with the neurologist in our primary hospital, or secondary care, whatever it’s called, in that hospital, he hadn’t seen that, so I’m telling him the results, which isn’t ideal, but it happens quite a lot. What I think is quite significant to me is the reaction to that VUS. I have to give it, the doctors that look after my daughter are brilliant, and I’m not criticising them in any way but their reaction to a VUS is “I’m so grateful for the persistence to get to a diagnosis.” Neurologists are a bit more like “Oh it’s a VUS so it might be significant, it might be nothing.” Actually, as a patient, as in a parent, you actually want to know is it significant or not, “Do I look at it or not?” And, I mean, like I said, there were no research papers to look at before anyway until a few months ago so I didn’t have anything to look at, but I didn’t want to look at it either because you don’t want to send yourself off down a path. But I think that collective sort of idea that once someone gets a VUS we need a pathway for it, “What do we do with it, what expectation do we set the patients up with and what is the pathway for actually researching further?” because this is where we really need the research. Adam: Thank you, Jo. So, Emma, over to you in terms of how best do you think clinicians can actually support patients at navigating this odyssey and what’s the difference between an initial diagnosis and a final diagnosis and how do you then communicate that effectively to the patients and their family? Emma: So I think a key thing for me, and it’s come up just now again, is that you need to remember as a doctor that the things you say at critical times in a patient’s or parent’s journeys they will remember – they’ll remember it word for word even though you won’t – and thinking about how to do that in the most sensitive, empathetic, calm, not rushed way is absolutely key. And there are some difficulties with that when you’re in a very high-pressure environment but it is absolutely crucial, that when you are communicating information about test results, when you’re talking about doing the test in the first place, you’re consenting the family, you’re explaining what you’re trying to do and those conditions, you balance how much information you give people. So, you were talking earlier about “So you haven’t got this diagnosis, you haven’t got that diagnosis,” I often think it’s… We’re often testing for numerous different conditions at the same time, I couldn’t even list them all to the parents of the children or the patient that I’m testing. It’s key to try and provide enough information without overwhelming people with so much information and information on specific conditions you are just thinking about as a potential. Sometimes very low down your list actually but you can test for them. Because people go home and they use the internet and they look things up and they get very, very worried about things. So, for me it’s trying to provide bite-sized amounts of information, give it the time it deserves, and support people through that journey, tell them honestly what you think the chance of finding a diagnosis is. If you think it’s u

In this special end-of-year episode of Behind the Genes, host Sharon Jones is joined by Dr Rich Scott, Chief Executive Officer of Genomics England, to reflect on the past year at Genomics England, and to look ahead to what the future holds. Together, they revisit standout conversations from across the year, exploring how genomics is increasingly embedded in national health strategy, from the NHS 10-Year Health Plan to the government’s ambitions for the UK life sciences sector. Rich reflects on the real-world impact of research, including thousands of diagnoses returned to the NHS, progress in cancer and rare condition research, and the growing momentum of the Generation Study, which is exploring whether whole genome sequencing could be offered routinely at birth. This episode offers a thoughtful reflection on how partnership, innovation, and public trust are shaping the future of genomic healthcare in the UK and why the years ahead promise to be even more exciting. Below are the links to the podcasts mentioned in this episode, in order of appearance: How are families and hospitals bringing the Generation Study to life? How can cross-sector collaborations drive responsible use of AI for genomic innovation? How can we enable ethical and inclusive research to thrive? How can parental insights transform care for rare genetic conditions? How can we unlock the potential of large-scale health datasets? Can patient collaboration shape the future of therapies for rare conditions? https://www.genomicsengland.co.uk/podcasts/what-can-we-learn-from-the-generation-study “There is this view set out there where as many as half of all health interactions by 2035 could be informed by genomics or other similar advanced analytics, and we think that is a really ambitious challenge, but also a really exciting one.” You can download the transcript , or read it below. Sharon: Hello, and welcome to Behind the Genes. Rich: This is about improving health outcomes, but it’s also part of a broader benefit to the country because the UK is recognised already as a great place from a genomics perspective. We think playing our role in that won’t just bring the health benefits, it also will secure the country’s position as the best place in the world to discover, prove, and where proven roll out benefit from genomic innovations and we think it’s so exciting to be part of that team effort. Sharon: I’m Sharon Jones, and today I’ll be joined by Rich Scott, Chief Executive Officer at Genomics England for this end of year special. We’ll be reflecting on some of the conversations from this year’s episodes, and Rich will be sharing his insights and thoughts for the year ahead. If you enjoyed this episode, we’d love your support, so please subscribe, rate, and share on your favourite podcast app. So, let’s get started. Thanks for joining me today, Rich. How are you? Rich: Great, it’s really good to be here. Sharon: It’s been a really exciting year for Genomics England. Can you tell us a bit about what’s going on? Rich: Yeah, it’s been a really busy year, and we’ll dive into a few bits of the components we’ve been working on really hard. One really big theme for us is it’s been really fantastic to see genomics at the heart of the government’s thinking. As we’ll hear later, genomics is at the centre of the new NHS 10-year health plan, and the government’s life sciences sector plan is really ambitious in terms of thinking about how genomics could play a role in routine everyday support of healthcare for many people across the population in the future and it shows a real continued commitment to support the building of the right infrastructure, generating the right evidence to inform that, and to do that in dialogue with the public and patients, and it’s great to see us as a key part of that. It’s also been a really great year as we’ve been getting on with the various programmes that we’ve got, so our continued support of the NHS and our work with researchers accessing the National Genomic Research Library. It’s so wonderful to see the continued stream of diagnoses and actionable findings going back to the NHS. It’s been a really exciting year in terms of research, publications. In cancer, some really exciting publications on, for example, breast cancer and clinical trials. Really good partnership work with some industry partners, really supporting their work. For me, one of the figures we are always really pleased to see go up with time is the number of diagnoses that we can return thanks to research that’s ongoing in the research library, so now we’ve just passed 5,000 diagnostic discoveries having gone back to the NHS, it really helps explain for me how working both with clinical care and with research and linking them really comes to life and why it’s so vital. And then, with our programmes, it’s been great to see the Generation Study making good progress. So, working with people across the country, more than 25,000 families now recruited to the study, and we’re beginning to hear about their experiences, including some of the families who’ve received findings from the programme. It’s really nice to see and hear from Freddie’s family, who talked to the press a bit about the finding that they received. Freddie was at increased risk of a rare eye cancer, and really pleasingly, it was possible to detect that early through the screening that was put in place. Again, it really brings to life why we’re doing this, to make a difference and improve health outcomes. Sharon: That’s an incredible 12 months. Diving into that Generation Study piece and for listeners who don’t know what that is, it’s a research study in partnership with the NHS that aims to sequence the genomes of 100,000 newborn babies. On an episode from earlier in the year, we had mum, Rachel Peck, join the conversation, whose baby Amber is enrolled on a study. Let’s year from Rachel now. Rachel: From the parents’ point of view, I guess that’s the hardest thing to consent for in terms of you having to make a decision on behalf of your unborn child. But I think why we thought that was worthwhile was that could potentially benefit Amber personally herself or if not, there’s the potential it could benefit other children. Sharon: Consent has been such a big area of focus for us, Rich, and Rachel touches on that complexity, you know, making a decision on behalf of her unborn child. Can you talk a bit about our approach to consent in the Generation Study and what’s evolving in that model? Rich: Yeah. It’s been for the whole study, really, starting out asking a really big question here, what we’re aiming to do is generate evidence on whether and if so, how whole genome sequencing should be offered routinely at birth, and that’s responding to a really ill need that we know that each year thousands of babies are born in the UK with treatable rare conditions. We will also need to see if whole genome sequencing can make a difference for those families, but we realise to do that, as with all screening, that involves testing more people than are going to benefit from it directly themselves. So, you have to approach it really sensitively. There’s lots of complicated questions, lots of nuance in the study overall. One of them is thinking really carefully about that consent process so that families can understand the choices, they can understand the benefits and risks. This is still a research study. We’re looking to understand whether we should offer this routinely. It’s not part of routine care at this point. The evidence will help decision-makers, policymakers in the future decide that. At the beginning of the programme, we spent a lot of time talking to families, talking to health professionals who understand the sorts of decisions that people are making at that time of life, but also are experts in helping think about how you balance that communication. That involved, as I say, a lot of conversations. We learnt a lot, lots of it practical stuff, about the stage of pregnancy that people are at when we first talk to them about the study, so that people aren’t hurried and make this decision. What we’ve learnt in the study, right from the outset, is talking to people from midway through the pregnancy so that they really have time to engage in it and think about their choice. So, it’s an important part of getting the study design right so that we run the study right. It’s also a really crucial element of the evidence that will generate from the study so that we can understand if this is something that’s adopted, how should we communicate about it to families. What would they want to know? What’s the right level of information and how do we make that accessible in a way that is meaningful to people from different backgrounds, with different levels of interest, different accessibility in terms of digital and reading and so on. There’s a lot that we’ve learnt along the way and there’s a lot that we’re still learning. And as I say, important things that we’ll present as evidence later on. Sharon: Thank you. It’s fascinating there are so many moving parts and a lot to consider when you’re building the design of a programme like this or study like this. Earlier in the year you had a great conversation with Karim Beguir about the developments of AI in genomics. Let’s revisit that moment. Karim: We live in an extraordinary time. I want to emphasise the potential of scientific discovery in the next two or three years. AI is going to move, let’s say, digital style technologies like coding and math towards more like science and biology. In particular, genomics is going to be a fascinating area in terms of potential. Sharon: So, Karim talks about AI moving from maths and coding into biology. Why is genomics such a natural area for AI? Rich: It’s really fascinating. I think it links a lot to how we think about genomics and how you get the most value in terms of health benefit and sort of the progress that we can see could come through genomics more generally. So, your genome, which is your DNA code, written in 3 billion little letters across each one of us, one copied from mum, one copied from dad, even just our genomic code of one person is a large amount of data. That is just part of the story because we’re not just interested in DNA for DNA’s sake, this is about thinking about health and how we can improve health outcomes. So, it’s also thinking about the other sorts of information that needs to link to genomic data to make a difference. Whether that’s just to provide routine healthcare with today’s knowledge, or whether it’s about continuing to learn and discover. As I mentioned at the beginning, I think a really important part of this whole picture is we’ve learnt a lot in the last 20/30/40 plus years about genomics. It’s incredible how much progress has been made, and we’re really just scratching the surface. Take rare disease and the progress that’s been made there, it’s wonderful how many more families we’re able to help today. We know that many thousands of families we still can’t find a diagnosis for when we know that there is one there for many of them. That theme of ongoing learning is at the centre of all of our work, and that will continue as we look about broader uses of genomics in other settings beyond rare conditions and cancer. It’s also that ongoing learning, but also the amount of, at the moment, manual steps that are required in some of the processes that we need to, for example, find a diagnosis for someone or to make sure the tools that we use are the most up to date, the most up to date with the medical literature, for example. AI is a tool that we’re, as the whole of the society, we’re beginning to see how it can play a role. We see it as important today for some of the just really practical things. I mentioned it, staying up to date with the medical literature, making sure that we and our systems are aware of all of the knowledge that’s coming in from around the world. It’s got real potential there. I think the biggest bottom line here is that it’s got the potential to be a really important tool in terms of our ongoing learning and improvement. I’m a doctor by background, the human intelligence alone is fantastic, it’s moved us a long way, but we know it also has tremendous blind spots. AI has the potential to complement us there. I guess another thing to really call out here, AI isn’t a panacea, it’s not suddenly going to answer all of the questions. And, just like human intelligence, it will have its own biases, have its own strong points, and less strong points. One of the things we’re really committed to is working with people like Karim, and many others, to understand where AI could make a difference, to test it, to generate evidence on how well it works and an understanding in all sorts of ways about how that might play out. And, make sure that as AI becomes a tool, that we in genomics, but also in other areas, we understand its strong points and where we need to be more careful and cautious with it. That’s a really important part of what we’re going to be doing in the coming years here, is making sure that we can maximise the impact of it, but also be confident, so that we can explain to people whose data we might use it on how we’re doing it and what it’s bringing. Sharon: Thanks Rich. It’s definitely a fast-moving conversation of which we really want to be part of. One of the things that’s come up again and again this year is participation and co-production. Let’s hear quote that really captures that. Bobbie: In an earlier conversation with Paul, which you might find surprising that it’s stuck with me so much, he used the word ‘extractive’. 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. Sharon: That was Professor Bobbie Farsides talking about moving away from extractive research towards true co-production. How are we making that shift in practice here at Genomics England? Rich: It’s a great question. It’s one of the areas where I think we’ve learnt most as an organisation over the years about how really engaging from the beginning with potential participants in programmes, participants who join our programmes, people who are involved in delivering our programmes and healthcare is so important at the beginning. I mentioned earlier the work to think about the consent process for the Generation Study, and that’s one of the areas where I think from our first programme, 100,000 Genomes Project, we learnt a lot about how to do that well, some of the pitfalls, some of the bits that are most challenging. And really, right from the start of our programmes, making sure that people who will potentially benefit from the programmes, potentially join them, can be part of that engagement process, and really part of the design and the shaping of the research questions, the parameters around research, but also the materials and how people will engage with them. And that’s one of the key capabilities we have internally as an organisation, so we work with partners externally, but also it’s a really key part of the team that we have at Genomics England. Sharon: So, whilst Bobbie talked about moving away from research that can feel one-sided and towards true collaboration, in another episode, Lindsay, a parent of a child with a rare condition, reflected on what that change really means for families and how it’s empowering to see their voices and experiences shaping future treatments. Lindsay: Historically, there’s been a significant absence of a patient voice in rare disease research and development. And knowing that that’s changing, I think that’s really empowering for families. To know that professionals and industry are actually listening to our stories and our needs and really trying to understand, that offers much greater impact on the care and treatments of patients in the future. Sharon: So, what role do you see participants as partners in shaping the next phase of Genomics England’s work? Rich: So, as you probably detected from my last answer, we see it as absolutely vital. One of the really exciting things here at Genomics England, we’ve had a participant panel from very early in our life as an organisation. That’s one really important route to us at the heart of our organisation, part of our governance, making sure that participants representing all sorts of parts of our programme, but rare conditions being a really large focus for us. And I think, what’s so striking as someone with a medical and a research background can see how I think historically medics and researchers have sometimes not known, sort of maybe been a bit scared about knowing how to involve participants from the outset. Often, because they’re worried that they might ask the wrong questions in the wrong way, they just don’t have the tools. One of the things I often say now to people we work with is one of the most empowering and positive experiences we have at Genomics England is the power of our participants helping to, right from the beginning, shape what the questions are that we should be asking. Realise some of the challenges that you can’t possibly, if you’re not in their shoes, understand are the most important to really shape how we prioritise our work internally, the problems that we need to solve first, how we think about some of the practical impacts on people’s lives that, again, without hearing from their voice you just wouldn’t know. And again, to help our researchers, people accessing data in the National Genomic Research Library, helping them make sure that they involve participants in their work and the confidence and tools to do that. Sharon: That’s great, thank you. Another big theme this year has been collaboration across the NHS, academia, and industry. Dr Raghib Ali puts this really well. Raghib: There are areas where academia and the NHS are very strong, and there are areas where industry is very strong, and why working together, as we saw, you know, very good examples during the pandemic with the vaccine and diagnostic tests, etc., a collaboration between the NHS, academia, and 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. Sharon: So, how does collaboration fit into the 10-year health plan and what’s next for 2026 in that space, Rich? Rich: I think one of the most enjoyable parts of my role at Genomics England and our role as an organisation is the fact that we see ourselves very much as part of a, sort of team across the UK and in fact internationally in terms of delivering on the potential we see for genomics. So, we have a vision as an organisation, which has been the same the last 5 or so years, which is a world where everyone can benefit from genomic healthcare. In fact, that vision is now shared by the NHS from a genomics perspective, and really demonstrably, the 2 parts of the system absolutely pointing in the same direction. And when we’ve been thinking, looking forward with that 10-year lens on it, what we always like to do, and I think it’s a real privilege to be able to do, because we’re here in the UK, because we have a National Health Service, because there’s been that long-term commitment from government on genomics and really taking a long-term investment view there, and because of so many other parts of the ecosystem, other experts who access data in the National Genomic Research Library, research organisations like Our Future Health, UK Biobank, all teaming together, and the expertise that’s the

In this explainer episode, we’ve asked Dr Katie Snape, principal clinician at Genomics England, cancer geneticist, and specialist in inherited cancer, to explain how genomics can help us understand cancer. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Flo: How can genomics help us understand cancer? I'm Florence Cornish, and today I'm joined with Katie Snape, who is Principal Clinician here at Genomics England, lead Consultant for Cancer Genetics at the Southwest Thames Centre for Genomics, and Chair of UK Cancer Genetics Group. So Katie, it's probably safe to say that everyone listening will have heard the word cancer before. Lots of people may have even been directly affected by it or know someone who has it or who has had it, and I think the term can feel quite scary sometimes and intimidating to understand. So, it might be good if you could explain what we actually mean when we say the word cancer. Katie: Thanks, Florence. So, our bodies are made up of millions of building blocks called cells. Each of these cells contains an instruction manual, and our bodies read this to build a human and keep our bodies working and growing over our lifetimes. So, this human instruction manual is our genetic information, and it's called the human genome. Throughout our lifetime, our cells will continue to divide and grow to make more cells when we need them. And this means that our genetic information has to contain the right instructions, which tell the cells to divide when we need new cells, like making new skin cells, for example as our old skin cells die, but they also need to stop dividing when we have enough new cells and we don't need anymore. And this process of growing but stopping when we don't need anymore cells, keeps our bodies healthy and functioning as they should do. However, if the instructions for making new cells goes wrong and we don't stop making new cells when we're supposed to, then these cells can grow out of control, and they can start spreading and damaging other parts of our body. And this is basically what cancer is. It's an uncontrolled growth of cells which don't stop when they're supposed to, and they grow and spread and damage other tissues in our body. Florence: So, you mentioned there that cancer can arise when the instructions in our cells go wrong. Could you talk a little bit more about this? How does it lead to cancer? Katie: Yeah. So the instructions that control how our cells should grow and then stop growing are usually called cancer genes. So our body reads these instructions a bit like we might read an instruction manual to perform a task. So if we imagine that one of these important cancer genes that has a spelling mistake, which means the body can't read it properly, then those cells won't follow the right instructions to grow and then stop growing like they should. So if our cells lose the ability to read these important instructions due to this type of spelling mistake, then that's when a cancer can develop. As these spelling mistakes happen in cancer genes, we call them genetic alterations or genetic variants. Florence: And so, when you're in the clinic seeing somebody who has cancer, what kinds of genomic tests can they have to help us find out a little bit more about it? Katie: So the genetic alterations that can cause cancer can happen in different cells. So that's why cancer can affect many different parts of the body. If a genetic alteration happens in a breast cell, then a breast cancer might develop. If the alteration happens in a skin cell, then a skin cancer could develop. We can take a sample from the cancer. This is often known as a biopsy, and then we can use this sample to extract the genetic information to read the instructions in the cancer cells, and when we do this, we are looking for spelling mistakes in the important cancer genes, which might of course, those cells to grow out of control. We can also look for patterns of alterations in the cells, which might tell us the processes that led to those genetic alterations occurring. For example, we can look at patterns of damage in the genetic information caused by cigarette smoke, or sunlight, or problems because the cell has lost its ability to mend and repair its genetic information. And we can also count the number of different alterations in the cancer cell, which might tell us how different that cancer cell is from our normal cells, and that can be important because we might be able to use medications to get our immune system to attack the cancer cells. So where we see genetic alterations in a cancer cell, we call them acquired or somatic alterations because we weren't born with them, but they've happened in a cell in our body at a later stage, and they've caused those cells to become uncontrollable and to keep growing. Sometimes people can be born with a genetic alteration in a cancer gene that significantly increases the chance of them developing cancer in their lifetime. This type of genetic alteration can be inherited, and so these changes can be shared by relatives. If we see more cancer in a family than we would expect by chance, or unusually young cancers or patterns of cancer, or there are other signs that a cancer patient might have an inherited cancer gene causing their cancer, then we can offer a test to check for this as well. Florence: And so, when we do these tests, what are we looking for specifically? What is it that we're trying to find out about a person's cancer that could help us to treat it as effectively as possible? Katie: So all of these genetic tests are helping us understand why a cancer has developed and what are the underlying changes that cause the cells to grow out of control. If we understand why the cancer developed, we can choose medications to try and treat the cancer and these specifically target the underlying problems in the cell, and hopefully attack the cancer cells, but not the normal cells in the body. We call this precision or personalised medicine. Many newer cancer drugs specifically target the changes that have occurred in the cancer cells as part of this process for becoming cancer, and they kill those that carry specific genetic changes which have caused those cells to grow uncontrollably. Florence: I wanted to ask you now about inherited cancer risk. So by this we mean if a parent has a change in one of their genes that increases their risk of developing cancer, there's a possibility that they can then pass this gene along to their children. Is there anything we can do to manage these inherited risks? Katie: If a person has an inherited change, increasing cancer risk, we can offer them programs to help reduce that risk. There are different things that we might offer them. So, for example, for some conditions we have preventative medication. There is a condition called Lynch syndrome, which is due to a change in some cancer genes, and people who have Lynch syndrome have a high chance of developing bowel and womb cancers, amongst others. For people with Lynch syndrome, they can take a daily low dose aspirin, and this reduces their chance of developing a bowel cancer by about a half. Or in other cases, we can offer extra screening and that will allow us to catch any cancers that do occur at an earlier stage when they're more likely to be more effectively treated. So for example, if someone has a high risk of breast cancer, we could offer them extra and more frequent screening of their breast. Another option is we could offer risk reducing surgery. So, for example, if someone had a higher chance of developing ovarian cancer after the age of 50, we could offer removal of the tubes and ovaries as their chance of cancer starts to increase, and that would significantly reduce their risk of developing cancer in the future. Florence: And, working in this space, you and I know that research groups are working all the time to try and better understand cancer and how we might be able to treat it more effectively. Could you tell me about how genomics in particular is helping to advance the detection and treatment of cancer? Katie: Genomics is helping develop both our understanding of how and why cancer develops, and as well as that, it's also helping us find new cancer treatments all the time. There are already many drugs that are available to cancer patients that specifically target the genetic changes found in their cancer. In addition to that, there are many clinical trials now for cancer patients, which use the information from genomic sequencing to help guide new research into better treatments based on the genetic alterations in the cancer cell. We are increasingly using genetic testing to identify more at-risk people with inherited changes in the population as well, so that we can make sure if they have a higher chance of developing cancer in their lifetime, that they get the best prevention and screening programs available. our understanding of genomics is really impacting both our understanding of what causes cancer, how we treat it, and how we can prevent it as well. Florence: So, I think we'll finish there. Katie, it's been so great to talk to you and to learn more about why genomics is proving to be so important in helping us to understand cancer. If listeners want to hear more, explain episodes like this, you can find them on our website@www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

In this explainer episode, we’ve asked Amanda Pichini, clinical director at Genomics England and genetic counsellor, to explain what a genetic counsellor is. You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel . If you’ve got any questions, or have any other topics you’d like us to explain, let us know on podcast@genomicsengland.co.uk. You can download the transcript or read it below. Florence: What is a genetic counsellor? I'm Florence Cornish, and today I'm joined with Amanda Pichini, a registered genetic counsellor and clinical director for Genomics England, to find out more. So, before we dive in, lots of our listeners have probably already heard the term genetic counsellor before, or some people might have even come across them in their healthcare journeys. But for those who aren't familiar, could you explain what we mean by a genetic counsellor? Amanda: Genetic counsellors are healthcare professionals who have training in clinical genomic medicine and counselling skills. So they help people understand complex information, make informed decisions, and adapt to the impact of genomics on their health and their family. They're expert communicators, patient advocates, and navigators of the ethical issues that genomics and genomic testing could bring. Florence: Could you maybe give me an example of when somebody might see a genetic counsellor? Amanda: Yes, and what's fascinating about genetic counselling is that it's relevant to a huge range of conditions, scenarios, or points in a person's life. Someone's journey might start by going to their GP with a question about their health. Let's say they're concerned about having a strong family history of cancer or heart disease, or perhaps a genetic cause is already known because it's been found in a family member and they want to know if they've inherited that genetic change as well. Or someone might already be being seen in a specialist service, perhaps their child has been diagnosed with a rare condition. A genetic counsellor can help that family explore the wide-ranging impacts of a diagnosis on theirs and their child's life, how it affects their wider family, what it might mean for future children. You might also see a genetic counsellor in private health centres or fertility clinics, or if you're involved in a research study too. Florence: And so, could you explain a bit more about the types of things a genetic counsellor does? What does your day-to-day look like, for example? Amanda: Most genetic counsellors in the UK work in the NHS as part of a team alongside doctors, lab scientists, nurses, midwives, or other healthcare professionals. Their daily tasks include things like analysing a family history, assessing the chance of a person inheriting or passing on a condition, facilitating genetic tests, communicating results, supporting family communication, and managing the psychological, the emotional, the social, and the ethical impacts of genetic risk or results. My day-to-day is different though. I and many other genetic counsellors have taken their skills to other roles that aren't necessarily in a clinic or seeing individual patients. It might involve educating other healthcare professionals or trainees, running their own research, developing policies, working in a lab, or a health tech company, or in the charity sector. For me, as Clinical Director at Genomics England, I bring my clinical expertise and experience working in the NHS to the services and programmes that we run, and that helps to make sure that we design, implement, and evaluate what we do safely, and with the needs of patients, the public, and healthcare professionals at the heart of what we do. My day-to-day involves working with colleagues in tech, design, operations, ethics, communications, and engagement, as well as clinical and scientific experts, to develop and run services like the Generation Study, which is sequencing the genomes of 100,000 newborn babies to see if we can better diagnose and treat children with rare conditions. Florence: So, I would imagine that one of the biggest challenges of being a genetic counsellor is helping patients to kind of make sense of the complicated test results or information, but without overwhelming them. So how do you balance kind of giving people the scientific facts and all the information they need, but while still supporting them emotionally? Amanda: This is really at the core of what genetic counsellors can do best, I think. Getting a diagnosis of a rare condition, or finding out about a risk that has a genetic component, can come with a huge range of emotions, whether that's worry, fear, or hope and relief. It can bring a lot of questions, too. What will this mean for my future or my family's future? What do you know about this condition? What sort of symptoms could I have? What treatments or screening might be available to me? So genetic counsellors are able to navigate all of these different questions and reactions by giving an opportunity for patients and families to discuss their opinions, their experiences, and really trying to get at the core of understanding their values, their culture, their expectations, their concerns, so that they can help that individual make an informed decision that's best for them, help them access the right care and support, adjust or find healthy coping strategies, or maybe even change their lifestyle or health behaviours. So it's really finding that balance between the science, the clinical aspects, the information, and the support. Florence: So obviously working in this space, I get to read about lots of incredible research all the time, and it feels like genetics and genomics seems to be changing and advancing day by day. So, I'd be interested to know what this means for you and for other genetic counsellors, what's coming next? Amanda: Yeah, so as we continue to see advances in genetics and genomics, there's, I think, a really increasing need for genetic counselling expertise to help shape how these technologies are used and with giving the right consideration for the challenges around what this means for families and for wider society. Genomics is also still growing the evidence base it needs to provide a consistent and equitable service. We're seeing digital tools being increasingly available to give people information in innovative ways, seeing huge advancements in targeted treatments and gene therapies, that are changing fundamentally the experiences of people living with rare conditions and cancers. And we're using genomics more and more to predict future health risks and how people might respond to certain medications. So, there's a huge amount that we're seeing sort of coming for the future. What's interesting is the 10-Year Health Plan that the government has set out for the NHS provides, I think, huge opportunities for genomics. For example, we'll see healthcare brought closer to local communities, genomics being used as part of population health, reaching people closer to where they are and hopefully providing greater access. But I think the key thing in all of this is knowing that genomics is really just a technology. It requires people with the right skill sets to use it safely and to be able to benefit everyone, and genetic counsellors are a huge part of that. Florence: And finally, in case anyone listening has been inspired by this conversation and wants to build a career like yours, what advice would you have to offer somebody hoping to become a genetic counsellor in the future? Amanda: To train as a genetic counsellor in the UK, you usually need an undergrad degree in biological sciences, psychology, or being a nurse or midwife. The background can be varied, but usually driven by a common thread, a desire to sort of improve healthcare experiences for patients and make genomic healthcare widely accessible and safely used for everyone. You can apply for the 3-year NHS scientist training programme, or there's also master's degrees offered through Cardiff University, for example. In general, I'd encourage people to check out the website for the Association of Genetic Nurses and Counsellors, and reach out to genetic counsellors to ask about their career and their journey as much as possible, as well as seeking opportunities to really understand the experiences of people living with rare genetic conditions, because that will help you understand the ways in which genetic counselling can have an impact. Florence: We'll finish there. Thank you so much, Amanda, for all of those insights and for explaining what it means to be a genetic counsellor. If any listeners want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk or wherever you get your podcasts. Thank you for listening.

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