Behind the Genes

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 pharma companies. They've upskilled themselves to learn so much about genetics. 

[00:18:04] Nicky: And it's just an absolutely incredible thing to watch. They're so, so inspiring.  

[00:18:09] Sharon: And from what I understand, Christina, you feel, you know, very passionate about Nicky in the same way, about your paths crossing in this way.  

[00:18:16] Christina: Oh, my, yes. Every time I see Nicky, I've met her a couple of times, like, in person now, I just cry. 

[00:18:22] Christina: I literally, we saw her at the UK meetup, and she walked in the door, and that was it. I was done. I was like, it's just meeting somebody who has changed so many lives and brought a community to other families. It's just amazing. And the support that Nicky's giving us weekly, daily, is just amazing. It is just life-changing for all of us. 

[00:18:49] Sharon Jones: It's such a powerful connection. So Ana Lisa, why is collaboration between researchers, clinicians, and families so valuable in the rare disease research space? You know, and what role do large scale research projects and data sharing play in discoveries like this?  

[00:19:06] Ana Lisa: Collaboration is completely incredibly valuable and for progress in the rare disease space where there's just so much still to learn. 

[00:19:16] Ana Lisa: So more than half of patients and families where, uh, they're seeking a potential diagnosis, we're not yet able to, to find one, and there's so much yet that we still need to learn, and collaboration in so many different spaces and directions and across different spheres enables this progress. So for example, the fact that we have a really connected, uh, National Health Service and really close working between the NHS and Genomics England so that we can, for those patients and families that, that consent to their de-identified data being shared in the National Genomic Research Library, be able to work with many, many different researchers, uh, whether they're academic, institutions, industry, and try and find all the patients that could benefit from a new diagnosis and, uh, potentially new therapies in future clinical trials. 

[00:20:21] Ana Lisa: And without that collaboration, it would be really, really hard to find all those people So because we sort of have a clinical research interface where we can go back to clinical teams and therefore to patients and families, even if there's a really, really ultra-rare condition with very few people known to have it that could be under different specialties in different regions, we would be able to contact their clinical team. 

[00:20:51] Ana Lisa: So I think that, that collaborative working with the NHS is really powerful across researchers worldwide. Like in this example where a group in Oxford and a group in US were able to make this finding and then all the other findings that are coming from it. And really, without being able to compare across thousands of genomes, one wouldn't have been able to see this, this particular signal and see that there were more than 100 patients, and that was really powerful. 

[00:21:20] Ana Lisa: If you just had one genome, you could never have made this novel discovery. I think the other thing is that, and Nicky will say that, you know, she, she then contacted her collaborators who also had access to, to, to data that had been shared by other families and could compare. And again, it's a whole sort of network across the globe. 

[00:21:41] Ana Lisa: And we know that there are going to be many more diagnoses to be found. But also, um, I think collaboration will allow us to find new, new treatments. So if we can start to design treatments that target the DNA and RNA at, at source, then actually you could collaborate and say, "Well, this type of genetic mechanism could be targeted in the same way, potentially across even more than one rare condition and reach even more patients." 

[00:22:13] Ana Lisa: And actually the power of collaboration across the ecosystem is that hopefully we'll end up with a pathway that can actually go from finding a new genetic finding, like Nicky and her team made, to helping all the people who could benefit from a diagnosis, having one, and then can one develop a treatment and get it to as many patients? 

[00:22:42] Ana Lisa: And, and I think that will really demonstrate the power of collaboration.  

[00:22:47] Sharon: Yeah. Absolutely, and it can only, you know, benefit those families who have to wait such a incredible amount of time.  

[00:22:55] Ana Lisa: There's been such a diagnostic odyssey, and as more diagnoses are made, it becomes obvious that there's, uh... 

[00:23:03] Ana Lisa: and it was, it's already well-described, the therapeutic odyssey. Um, but hopefully these sort of novel understanding of our genome and opening up new biological avenues to treat, um, hopefully will also enable many more new treatments to be developed.  

[00:23:21] Sharon: Absolutely, and that is the key word there is, is that hope. 

[00:23:24] Sharon: So, so looking ahead, Nicky, what developments are you most hopeful about over the next few years?  

[00:23:31] Nicky: That's a difficult question. There's so much, so much happening. One thing is that we are gearing up to do large scale studies across the world to understand more about the progression of ReNU. So you might call them large scale natural history studies or just large scale profiling studies where we can do a range of different tests on ReNU patients and, and monitor them over time. 

[00:24:02] Nicky: So do those at regular, regular intervals over time so we can see what the progression looks like. And that's really important for trying to think about whether we can treat RNeU syndrome. And on that note, I'm very also excited about the potential for therapeutics. There's lots of people all around the world, both, uh, in academic settings, but also in pharma companies trying to work out whether this is something that we can treat. 

[00:24:30] Nicky: There's some very promising early data to show that we can selectively remove the RNA containing the mutation from cells, uh, leaving the copy of the RNA that doesn't contain the mutation intact so that can do the correct function. And biologically, we think this should be an effective treatment. 

[00:24:54] Nicky: Um, so we can do that in cells in a dish. We don't yet know whether we can do that in a patient with ReNU. Uh, but that's really, really promising early data. Um, so I'm very hopeful about where that, those studies might lead.  

[00:25:08] Sharon: And Ana Lisa, what role will genomics continue to play in improving understanding and care for rare conditions like this? 

[00:25:15] Ana Lisa: So following on from what Nicky said, I think the really big hope is that we will be able to develop many, many new treatments collaboratively across the world. And whether these are individualised treatments made for one patient but then shared because we can find perhaps other patients who could benefit from the same treatment, whether we understand the genetics better so that we can design treatments from the start that will work for a lot of patients. 

[00:25:46] Ana Lisa: So I think there will be sort of fancier and fancier ways of targeting rare conditions. And right now we're in a phase where the ecosystem is trying to work out how could we make an end-to-end pathway with initiatives like the Rare Therapies Launchpad in the UK, and that's going to require truly collaborative working. 

[00:26:08] Ana Lisa: No single organisation can do that. And I think having these incredible use cases will be really powerful for turbocharging the development of these pathways. And the hope is that once you've worked out how to do this across a range of different rare conditions, that one might reach a stage where one could do that a lot faster for many other rare conditions. 

[00:26:35] Ana Lisa: Because at the moment they're so underserved in terms of treatments available and there's a huge gap between being able to make a genetic diagnosis and then having treatments. The big hope is that understanding the genetics better will help to open up new pathways to treatment. I do hope that we'll also understand other aspects. 

[00:27:02] Ana Lisa: So for example, it might be that understanding the genetics better also helps us to understand different ways a condition might manifest in somebody, why it may be different from one person to another, why somebody might be more mildly affected and somebody perhaps more severely. And that might, may also help us to understand ways to treat a condition by getting, gaining these insights which are, are useful in and of themselves and may also lead to new therapeutic, uh, possibilities. 

[00:27:36] Ana Lisa: I think that would be one of my hopes that a lot of these areas overlap and lead to real benefit for patients and families, that we can translate that hope into concrete improvements in treatment for rare conditions. 

[00:27:57] Sharon: Do you have a sense of time, how long you think this could all take, that amount of collaboration? 

[00:28:06] Ana Lisa: Yeah, and I think this is actually another reason why sometimes it's quite tricky to make progress in this area because being able to predict those timelines is notoriously difficult when you look back historically. I'd like to hope that we're on the cusp of having an explosion of novel treatments that can target DNA and RNA, for example, or treatments that target something in the underlying biology that we now understand that we didn't before. 

[00:28:34] Ana Lisa: And I do think that there is going to be a big shift. But I think that the sort of confidence intervals around how big that range of time might be is very hard to predict. And that's why I think Christina and Nicky being able to share these stories and about their collaborative working really shines a spotlight on, on what could be done and how progress can happen. 

[00:29:02] Ana Lisa: That's really exciting. The other day at a conference, someone from industry stood up and said, "Oh, actually, we set up a clinical trial in the UK because we knew there were patients who could benefit from our work in the National Genomic Research Library," and that was really exciting for us because that's what we want to do; move forwards the opportunities for treatment for patients. 

[00:29:28] Sharon: And so finally, Christina, as a parent and member of this community, what are your hopes for the future, and what would you say to families who may still be searching for answers today?  

[00:29:39] Christina: It is a long journey, but there is the support and the help out there. If you have any inclination that you think you might have ReNU, reach out to your paediatrician or your doctor to see if you can get your genetic testing done because it's fighting to get the test, to go to people and say, "I think this is what we may have. Can we look into getting it tested?" And reach out to other families and the website and things because it's all about community and supporting and helping people find that diagnosis.  

[00:30:16] Sharon: Thank you, Christina, and we'll put the website in the episode description. A huge thank you to Professor Nicky Whiffin, Christina Cox, and Dr. Ana Lisa Tavares for joining me today and sharing their insights and experiences. To learn more about ReNU Syndrome, visit renusyndromeuk.org. If you'd like to hear more stories about the people, research, and discoveries helping to shape the future of healthcare, subscribe to Behind the Genes on your favourite podcast app. 

[00:30:45] Sharon: Thank you for listening. I've been your host, Sharon Jones. Behind the Genes is produced by Deanna Barac, Florence Cornish, Sophie McLachlan, and Katie Revell at Bespoken Media.

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 significantly reduce the risk of bleeding as well.

[00:17:37] So it was a manageable risk. It was something we could share with people. They knew they were taking a bit of a chance. But actually a good way of putting it in terms of the risk, for people in middle age, the risk of a low dose of aspirin is about the same as the risk of having a colonoscopy, which is very small, but it isn't completely without risk.

[00:17:56] Sharon: Yeah, and Drew, kind of like hearing this sort of incredible, like, backstory about how we've got to these trials and where we are today What was your experience like as a kind of participant of this trial?

[00:18:08] Drew: I understood I was going to be on 100, 300, or 600, but wouldn't know for at least three years, or was it five years? I can't remember.

[00:18:15] And then sometime later in the post we got these packs, and it was ... I remember at the time thinking it was like a rather dull advent calendar - ... in that you'd have the days of the week- ... with the little, with the little windows, and you'd, you'd pop the tablets out three times a day and take them.

[00:18:31] So I did that. I think, you know, I, I don't think I ever missed a day or whatever. Initially, I thought I must be on a really low dose, because I didn't actually notice any side effects. You know, I remember saying to my wife, I said, "Oh, I think I must be on the lowest dose, because I don't see any side effects."

[00:18:46] It was a surprise years later when I was told actually I'd been taking 600, so.

[00:18:51] Sharon: Wow.

[00:18:52] Drew: It was quite an easy experience really.

[00:18:54] John: We had a lot of problems. We had to pack the aspirin in six-month packs, because it was very expensive to pack this stuff up. It cost... We got the aspirin free from the Bayer company, but it cost us more than a million pounds to actually put it in, in the packs to satisfy the regulations.

[00:19:10] Uh, and a lot of people complained that the packs were a bit big and awkward, but that was just, you know, a constraint. But it was not that big a deal once people got into it. But we did get a lot of complaints about the size of the packets, which we couldn't do anything about that.

[00:19:24] Drew: They came regularly through the post, and, you know, so every three months or whatever I got another supply, and I just carried on taking them.

[00:19:30] Yeah, so.

[00:19:31] Sharon: What was going through your mind when you were kind of waiting for this potential outcome, Drew? Because you, like you say, it was, you know, it was a long time taking part. What was... Especially as you were opening your, you know, your package a day, knowing exactly what you were going to get.

[00:19:44] Drew: Well, I, I kind of knew it would be a long-term thing.

[00:19:47] I think I was committed for five years initially. But I carried on taking the aspirin for another probably five years after that. So yeah, I was just sort of happy to take the aspirin and then sort of wait to see what the results would be. As I say, that I didn't really notice any side effects, so I wasn't really worried that it was having any detrimental effect on me.

[00:20:09] So I was curious to see what the, what the results would be.

[00:20:12] Sharon: Yeah. John, the trial has provided like the evidence that, you know, low-dose aspirin can prevent bowel cancer. But are there any challenges that still exist with translating this research into clinic and ultimately patient care?

[00:20:26] John: Well, yes, and I'm going to hand back to Katie, who's actually leading the charge on, on getting it into practice as well.

[00:20:32] But just to say that I, I'm actually now literally on my other computer finalising my bid to go back to Cancer Research UK because we want to go for three more years. Wow. We said that we would follow people for 10 years after they'd finished their ... or after they'd started, so, you know, for at least 10 years.

[00:20:50] So the last person to join didn't finish until 2024, so we won't get to that person. It's Robin and one of my patients. We won't get to Robin's 10-year anniversary until 2029. Oh, yeah. By which time, obviously, Drew will be even further on. But that will give us at least 10 years of follow-up because we know that there is this delayed effect, and that was seen right back at the beginning when people looked, for example, the nurses study in America, where they followed 86,000 nurses and just asked them if they took aspirin.

[00:21:18] And nothing happened for 10 years, but those who were taking aspirin for more than 10 years saw a benefit. So in the general population, it probably takes that long to kick in. And so we need to keep going for just a while longer. It's not as expensive now because we're not giving people aspirin anymore.

[00:21:33] Sharon: Yeah.

[00:21:34] John: But one of the reasons we g- we made Drew's dose blind was because we wanted to know what the side effects would be when you didn't know how much you were getting There's a danger if you're getting a higher dose, you're more likely to complain. And actually, it did work out that the people on the lowest dose had the fewest side effects, even slight side effects.

[00:21:51] The only thing we can't escape from is if you're taking aspirin, you get bruising more easily because it blocks the platelets, which are the little tiny blood cells which plug up little holes in your blood vessels when they leak. The good news is we now know that platelets turn out to be right, a major factor in triggering cancer.

[00:22:09] And so the aspirin, by blocking the platelets, is actually reducing the risk of cancer, but also reducing the risk of cancer spreading in the body. So this is new research, and we've got another big research project in collaboration with a team in Cambridge who are, uh, pursuing this. Also, the other exciting news is that my other partner, Ruth Langley, is running a big trial of people with cancer, and those who are given aspirin as part of their treatment have less likelihood of getting spreading cancer later on.

[00:22:39] So the aspirin is clearly doing something good at many levels in the system. Surprisingly, and we think it might be partly, partly because we used to have a lot of salicylate in our diet, which is what aspirin's made from. And we think that maybe we're putting back something that the body actually was used to having.

[00:22:57] Yeah. But modern diets don't contain any, any salicylate because of the way we prepare our food. So it may well be that a little bit of aspirin's a good thing for everybody, but obviously, that's a choice that each person will have to make.

[00:23:09] Sharon: Yeah. I mean, it's a real powerhouse of a, of a drug essentially, which you're finding out more about its benefits as, uh, as research goes on.

[00:23:18] So Katie, can you just give us a bit of a broad overview of Genomics England's new adults program, which is kind of looking at this sort of area of work and, and what, how can it benefit people?

[00:23:29] Katie: Yeah. Thank you, Sharon. So, the adults programme at Genomics England is being funded by government, and the government wrote about it in the 10-year NHS Health Plan, the Life Science Sector Plan to run a large-scale genomics population study.

[00:23:44] So looking at how we can obtain genetic information from people in the population and look at more proactive and preventative healthcare, and can we generate evidence on where, how, and why the NHS should start applying genomics into kind of more population health measures. So, there's sort of two sides to this.

[00:24:05] So the first is thinking about pharmacogenomics, which is basically about how genetic factors influence how we respond to drugs. So lots of people have had experiences of having side effects from drugs, we've just been talking about that with aspirin, or for drugs not working so well for them. And we know that there are certain drugs that genetic factors can influence whether you should take the drug at all, or if you do, what dose you should take, whether it's going to work for you or not, whether you might be more likely to get side effects or adverse reactions.

[00:24:34] So part of the programme's looking at that. And then the other half of the programme will be looking at sort of is, are the genetic factors relevant for sort of serious and high-risk conditions in the adult population? So we could take bowel cancer as an example of that, a common condition, breast cancer, you know, common cancers or cardiovascular disease.

[00:24:58] We know there are certain genetic factors for some people that have significantly increased their chance of developing those serious adult onset conditions. Can we find those people in the population and then put measures in place to prevent that? So, you know, even just thinking about Drew's story, he didn't have a family history of cancer.

[00:25:16] The first time that he knew he had Lynch syndrome, he'd already developed bowel cancer. And we know that many people that have Lynch syndrome or other high-risk cancer genes are unaware of their status in the population, and so, um, the idea of this program is to really look at, well, if we were to, to look for some of these very high-risk genes in the general population, could we then put measures in place to reduce the chance of them developing the serious condition as a consequence?

[00:25:44] So instead of Drew presenting with his bowel cancer, we'd actually already picked it up, despite the fact he doesn't have a family history, and we'd offered him, let's say, aspirin if we'd known the information at the time, and we could maybe have prevented him from developing bowel cancer.

[00:25:58] So it's really exploring looking at that a little bit more.

[00:26:02] Where can we get genetic information in the population? Where might there be a really well-evidenced, like all the work John's done over 40 years, is really well-evidenced now. Yeah. Yeah. Where are there these opportunities for us to turn the dial on some of these common adult onset conditions?

[00:26:20] Sharon: What other challenges do you think with getting this out there do you see?

[00:26:25] Katie: Uh, I think there's, there's lots of challenges. I think it's a really com- ... complex programme of work. The first thing is that the risks might be different for people in a population than have a family history. So where I've worked for, for years, and John as well in, in clinical genetics, we've seen the highest risk people, the people with lots and lots of cancer in their family because they're the people that are presented to healthcare services. So we've worked out the risks based on that population. It will be really different when we move to the population setting. We'll find fewer people, and the risks might be lower because there might be other factors that are giving them a lower risk. But that's not to say the risk is zero.

[00:27:05] It's probably still raised. So then what we need to do is we need to consider, okay, well, what can we do to intervene, taking into account this change of context from people that we found through clinical services to people that we see in the population. And aspirin is a great example of this.

[00:27:22] So, you know, if we find that someone has a Lynch syndrome gene, then taking aspirin, unless there's a really good reason for them not to take aspirin, is almost certainly going to be low cost to the NHS and really significantly reduce the chance of them developing bowel cancer with a low risk profile. So where are those opportunities?

[00:27:41] And that isn't clear cut, and that's why we need a large scale research programme that can try to help the NHS answer some of those questions, so it can decide how best to spend its money in, in the people that are most likely to benefit from it with the least amount of risk or harm to them.

[00:27:58] Sharon: That makes sense. And, and so, you know, going to you, Drew, what are your kind of thoughts on some of the challenges that Katie's highlighted? And is there anything else that you think needs to be improved in better supporting people living with inherited risk of cancer in the future?

[00:28:14] Drew: In the brief sort of 10, 15 years or whatever since I've been s- suffering, awareness has increased greatly.

[00:28:21] I mean, for example, my GP now knows about Lynch syndrome, whereas I don't think she did when I was first diagnosed, and I think there is a little bit more awareness out there, but I still think it's a lot less than there would be for, say, for breast cancer. So for example, when a high-profile personality reveals they've got breast cancer, you often get information about inherited risks.

[00:28:44] You don't seem to get that with colon cancer. You know, when it's announced that so-and-so has died or is whatever, you don't get that same, you know, it, it might be a genetic thing. I mean, when I was first told people that I had bowel cancer, the response I got usually was, "Oh, poor diet, was it?"

[00:29:04] And I always felt a bit upset, that, you know, actually my diet was fairly healthy. And that was the assumption that people had. So I think anything that gets the message out there that there is a risk, an inherited risk, I'm not sure what the statistics are now, Katie, is it one in 400 people might be a Lynch syndrome carrier or something like that?

[00:29:24] You know, it's relatively high for something that is, if you know in advance you're at risk, you can do something about it. But like me, you know, I waited until it was too late, because I didn't know, and then had to have the surgery, so anything that promotes the message that there is a risk. I know some people don't want to know about their genetic makeup. Obviously, that's a choice. But I think to give people, as many people as possible, the choice must be a good thing.

[00:29:54] Sharon: Yeah, absolutely. And I think one thing I've noticed through this thread is the sort of theme of funding and what gets funding and the amount of time it takes to, to kind of get that funding.

[00:30:05] Is there anything you wanted to add around the kind of funding model, around why some things get funded, you know, uh, more prominent, like Drew's point, obviously, talks about if someone high profile kind of comes forward and says XYZ, that gets the spotlight shone on it, and there might be research going that direction compared to s- to, to other cancers.

[00:30:23] John: So maybe I could speak at that. So partly because of my experience, I've now been made chairman of the grant committee at Cancer Research UK for prevention and population research. And there is a real drive to push more resource into prevention for the obvious reasons.

[00:30:39] Katie: Yeah.

[00:30:39] John: And also, it's got to be remembered, it's very difficult for the drug companies to fund this because it takes such a long time that the drug's- Mm

[00:30:46] out of its patent before they actually get to use it. So, it's very difficult from a business point of view to fund research into prevention. But they are keen to help us, uh, but we really need sort of central government and the charities to focus on prevention if it's going to make a difference.

[00:31:02] And just on Drew's point on diet, I mean, diet is still important even if you have Lynch syndrome. In our CaPP2 trial, the people who were overweight were more than double the risk of cancer. So it's not like an either/or. If you've got a higher genetic risk and you have a bad diet, then that's, you know, is going to contribute.

[00:31:21] But the other exciting thing is, of course, we now have medical ways of treating obesity in, in people. So, one of the interesting areas is whether we should be, in the same way as we are for other high-risk populations with overweight, we should be giving overweight people with Lynch syndrome, help to lose weight because that will also reduce their risk.

[00:31:41] It's also worth just dropping in at the last moment here is that this is also a good news story in terms of treatment and further prevention. We now have a new class of drugs called immune checkpoint inhibitors, which specifically target the types of cancer that Drew had and are much more effective in curing them And also, we've just been given funding to do a project called LynchVax, which I'll be helping with, but it's led by David Church in Oxford.

[00:32:05] And this is developing a vaccine against cancers in people with Lynch syndrome. The great news is it'll probably work alongside aspirin because we know the aspirin is enhancing the immune response. So the two together may make this a curable condition.

[00:32:18] Sharon: That's actually incredible. I mean, that, it gives so much hope for people.

[00:32:23] And I just wanted to find out if you had any more kind of reflections as we close, because we're going to come to the end of our podcast today. If there's anything more that you wanted to share, anything that has been missed, or anything that you want our listeners to know, and I think I'm gonna come to you, Drew, first, because you're the person who's had to sort of live through this and, and go through this journey along the way.

[00:32:41] Drew: I think just basically, if you're not sure, get tested. Obviously, there are financial constraints. I'm sure that running a DNA test is quite an expensive business. But I think if you've got any history of bowel cancer in the family, you've got any concerns about your health, speak to a GP and see if you can get tested as quickly as possible.

[00:33:00] And then, to get a better message out there that there are risks of inherited colon and other similar cancers, so.

[00:33:11] Sharon: Yeah, so it's getting that, messaging out, um, for people to understand more and make those informed choices. And Katie?

[00:33:18] Katie: I mean, I would say that the power of, of our, you know, NHS and our academia and, and our healthcare system has been collaboration.

[00:33:26] Sharon: Yeah.

[00:33:27] Katie: There's so many moving parts. There's commissioners, there's funding, there's the evidence, there's research, there's healthcare implementation. The UK's a really amazing place to work in genomic medicine, and I think that's partly because of the amazing collaborations that we have, and the way that we can translate research into healthcare as John's team have done with this amazing study.

[00:33:48] So let's all keep working together, please.

[00:33:52] Sharon: Absolutely. And John, it feels like this is your lifetime's work.

[00:33:58] John: Well, I've become aspirin man, it wasn't intended. But Katie's done fantastic work in her role as chair of the Cancer Genetics Group in the UK, so we've now implemented a,

[00:34:06] we're the first in the world to really make this an absolute directive to the GPs and all, to all doctors to say, "People with Lynch syndrome need to be offered aspirin." And so that's a great step forward. But we also need to get it into the British National Formulary, and I'm working with their team so that the GPs are empowered to do this.

[00:34:24] It's actually part of their care package. But I would just say we've still got a long way to go. We've now got a national list of all the people with Lynch syndrome, like Drew, to make sure we offer them all a colonoscopy, but there are only 14,000 people after several years of really pushing.

[00:34:40] Sharon: Right.

[00:34:40] John: We think in the national population in all ages, it's about 1 in 300. That's a lot of people. That means there's about 150,000 people like Drew in the country, and we've only found 10% of them. So we can't just rely on family history for all the reasons Drew explained. You know, I mean, Drew's dad probably died of Lynch syndrome, but we don't know because we've lost that record.

[00:35:02] So now we're checking every bowel cancer to see if it might be caused by Lynch, and that programme is now kicking in, and we're picking up a lot more gene carriers as a result of that. But there's still a long way to go to get co- get people aware of Lynch syndrome, to think of it when someone presents with a cancer, not just of the bowel, but in the womb, in the kidney, in other parts of the body.

[00:35:23] It's not just the bowel, but that's the most important group.

[00:35:26] Sharon: Yeah.

[00:35:26] John: So there's still a long way to go.

[00:35:28] Sharon: Where you've come to now is still an incredible achievement, even though we've still got a long way to go, and I don't think we should ever lose sight of that. So we're going to wrap it up there. Thank you to our guests, Katie Snape, Professor Sir John Burn, and Drew Hyde, for joining me today as we discuss cancer prevention.

[00:35:48] If you'd like to hear more like this, please subscribe to Behind the Genes on your favourite podcast app, and thank you for listening. I've been your host, Sharon Jones, and Behind the Genes is produced by Deanna Barac, Florence Cornish, Sophie McLachlan, and Dave Howard at Bespoken Media.

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. 

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