Episodit
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In this explainer episode, weâve asked Marie Nugent, Community Manager for the Diverse Data Initiative at Genomics England, to explain what diversity is and why it's important, in the context of 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 youâve got any questions, or have any other topics youâd like us to explain, feel free to contact us on [email protected].
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/006-Why-is-diversity-important-in-genomics-research.docx
Naimah: Why is diversity important in genomics? Today, Iâm joined by Marie Nugent, whoâs an engagement manager for the Diverse Data Initiative at Genomics England, and sheâs going to explain more. So first of all, Marie, letâs start at the beginning. What is diversity?
Marie: I think itâs sort of a fiendishly seeming simple question, isnât it, what is diversity, and I think youâll get just as broad a range of answers as the people you might ask that question to. But for me, you know, itâs really got to be about how we do things. So to me, diversity is about recognising that thereâs maybe a limited way in which certain things work, or the way in which we might go about doing certain things, and itâs also limited in terms of whoâs involved in that and who might benefit from that. So, in the broadest sense, I think diversity means recognising the limitations of maybe what you currently do, and really looking for how can we open that up a lot more to provide the space and opportunity for a broader range of people and voices and experiences to really be brought into that and shape it.
Naimah: And can you tell me a bit more about what diversity means in the context of genomics?
Marie: I find this absolutely fascinating in the context of genomics, because genomics is really about how do we understand, you know, how our DNA, as an entire piece of information, is building us and shaping us as people, and having an impact on our lives, and, you know, for us predominantly our health. And the way in which we currently think about grouping people in genomics is unfortunately still very, very heavily influenced by social understandings of how people group together, not necessarily anything thatâs really about your genetic ancestry, for example, which is very different. So at the moment, you know, itâs an interesting thing to play with and think about because in genomics itâs absolutely crucial that we understand the broadest sense of human diversity in terms of genetics and genomics, and only by doing that can we start to really fully understand what it means to be distinct, and therefore how small changes in DNA can have a massive impact on peopleâs health.
So, diversity in the context of genomics has to actually completely change the very fundamental ways in which we currently understand how people group together, so itâs really getting at the heart of that academic thinking about the topic. But itâs more than that, of course, as well, because as Iâve sort of already mentioned about what diversity means more broadly, itâs got to be about how we do things and whoâs involved in that, and who benefits from it. So, in the context of genomics, itâs playing at the ideas of how we even understand how people relate to each other and how theyâre different from each other, as well as how we do things. Itâs a really complex but fascinating topic, to be honest, to be able to look at and study in some way.
Naimah: How does the inclusion of diverse populations contribute to improving genomic research?
Marie: Yeah, so following on from what Iâve just said, we fundamentally need to include everyone, you know. In order for us to really understand what genetic ancestry means and what difference looks like across different groups, and how that impacts health, we have to be able to capture, as best as we possibly can, you know, what true genetic diversity looks like in people. So, including as many people as possible who are different from what we currently understand is absolutely crucial. Itâs the only way in which we can progress this area. And as I say, thatâs in terms of how we think about it maybe academically and what we can do in terms of research, and what we understand, but itâs got to also be about the practice and how we do things. So, thereâs involving people and having good representation of people in, say, data, but we have to think about how weâre involving people in how we do things and how we understand things, and how we make decisions about these things too.
Naimah: So, for these large groups of people, what are the challenges and barriers for including everyone?
Marie: So, I think there are a lot of challenges and barriers that hinder the inclusion of a broader range of groups of people in studies. I suppose the main one that Iâm going to focus on is itâs actually the way in which we do research. Itâs actually our culture, if you like, of work in this area. Thatâs one of the biggest barriers, and thatâs because, you know, research is a very fast paced, very competitive environment and area of work to be in. Quite often, you know, things need to be done at pace, and things need results, and things need to be published and all that sort of thing, and I think there is sometimes this perception of not having enough time to slow down a little bit, think a bit more carefully and outside the box about how we might approach a piece of work, for example.
So for me, I think the biggest barriers actually exist within the existing organisations and people who do this work currently. Weâre quite sort of blinkered, I think, still in terms of how we can even approach this work. And finding ways of approaching doing research in a way thatâs kind of outside the traditional sort of ways of thinking is for me personally, in my experience of working in this area, one of the biggest challenges still.
Naimah: And finally Marie, how can we address these challenges?
Marie: I think itâs not easy for sure, because this isnât a new thing that people have been trying to do, you know. Thereâs a big body of work, you know, in the context of the UK thatâs been going on for a number of years, thatâs been about sort of trying to open up and challenge, you know, existing research culture and things like that. But I think it has to be about our approach. So, for example, we have the power at Genomics England to think about how we approach the new initiatives, the new pieces of work that we would like to initiate. We talk about trust a lot in this space, but for me, it has to link back to how do we therefore change the way in which we do things so that it opens up a little bit more, people can see for themselves that weâre trustworthy and they can trust in this, rather than just saying, âObviously, you can trust us because weâre doing research,â or, âWeâre doing something thatâs going to be brought into the NHS.â Unfortunately, that just doesnât quite cut it for a lot of people for various fairly understandable reasons.
And I think, you know, we can make decisions about how we go about doing that work, and I think itâs about your priorities and things like that. So for me, the most effective way of actually addressing some of these existing challenges and barriers is to almost be brave enough to do it differently, and take that sort of perceived risk of maybe not doing things as expected and slowing it down, and allowing that extra time and space for people to come in and shape it, and not actually feel like we have to know everything and we have to make all the decisions. Sometimes I think itâs about, we hold the space, we have the resources and we have the access to the expertise, but how can we create the space where actually other people shape it and we just simply facilitate it. Thatâs the kind of thing Iâd like to see organisations like ours and other research institutions and things like that start moving towards as facilitators of shaping work that will bring some sort of public benefit.
Naimah: That was Marie Nugent explaining diversity in genomics. Iâve been your host, Naimah Callachand, and if you want to hear more Explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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In this explainer episode, weâve asked Ellen Thomas, Interim Chief Medical Officer at Genomics England, to explain what genetic and genomic tests are, why someone might do a test, and how they are performed, in less than 10 minutes.
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 youâve got any questions, or have any other topics youâd like us to explain, feel free to contact us on [email protected].
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/005-What-is-genetic-or-genomic-testing.docx
Naimah: What is genetic or genomic testing? Today, Iâm joined by Ellen Thomas, interim chief medical officer for Genomics England, whoâs going to explain more. So, first of all Ellen, what is a genetic test?
Ellen: Well, genetic tests examine a personâs genes to see if they have any changes in their DNA which might explain their symptoms. We all have DNA in most of the cells of our bodies, we inherit it from our parents and pass it on to our children. DNA provides the blueprint for our genes, and the proteins which build and run our bodies. Nearly all of our DNA is exactly the same across all of us, but around 5 million out of our 3 billion DNA letters are different, and each of these we call a genetic variant. The pattern of genetic variants that we all carry helps to make us who we are, and genetic testing is designed to examine some of these variants to help inform our healthcare.
Naimah: So, why are they sometimes called genetic tests and sometimes called genomic tests?
Ellen: Well, the words genetic and genomic are often used in exactly the same way, but broadly, genetic tests are usually used to look at just one or a small number of a patientâs genes, while a genomic test will look at hundreds or even thousands of genes at the same time. In general, itâs fine to use either.
Naimah: If you want to hear more about the difference between genetics and genomics, you can find another explainer episode with Rich Scott on our website, which goes into more detail.
Okay, so coming back to you, Ellen, what are the reasons we might do a genomic test?
Ellen: Some rare health conditions are caused by DNA variants in our genes, conditions such as cystic fibrosis, Huntingtonâs disease or sickle cell disease. In these 3 conditions, there is usually just one gene that is responsible, the same gene for all patients. That means that you can often find the DNA variant which has caused a patientâs symptoms by doing a test which looks just at that gene, or even sometimes just at a part of the gene. But for other genetic conditions, a variant could be found in any of dozens or even hundreds of genes, which could cause the same condition or a group of conditions, and examples of that include familial forms of epilepsy or developmental disorders in children.
For these conditions, to find an answer you often need to do a broader genomic test, looking at many genes at the same time, and also sometimes in between the genes. Finding the variant in a patientâs DNA which has caused the condition is useful, because it helps understand how the condition is passing down in the family, and whether it could affect anyone else in the family in the future. It is also increasingly used to work out which treatment an individual patient might respond to best.
Genomic tests are also used to help diagnose and treat cancer. A tumour develops and spreads because new variants in the DNA build up inside the tumour, which are not present in the patientâs healthy cells. By testing the DNA of the tumour, you can sometimes understand more about why it happened and what treatment might be most effective.
Naimah: So, can you tell me a bit about what sort of questions you can and canât address with genomic testing, and how has this changed over time?
Ellen: Well, at the most basic level, if a condition is not caused by DNA variants, then a genomic test will not provide any useful information. So, doctors use genomic tests when they suspect that a patient might have an explanation of their symptoms in their genes, but we donât always find an answer. Sometimes patients with a genomic cause and those with a different cause may have very similar symptoms.
We do constantly learn more about the ways in which genetic variants cause disease through research. Patients may have a gene variant causing their condition, but itâs so rare that it hasnât yet been discovered, or so complex that it canât be seen in the test analysis, so the test wonât identify the cause. Sometimes new understanding through research can then find the answer, which can be many years after the patient first developed symptoms.
Naimah: And how are these tests performed? For example, are they a blood sample?
Ellen: Yes, for most rare conditions, the tests use a blood sample. In cancers, a sample of the tumour needs to be tested after itâs removed by surgery or biopsy. The blood or the tumour is then processed to extract the DNA, and then thereâs a range of different tests which can be used to read the DNA sequence. Expert scientists in the NHS then review variants in the DNA to make sense of the results and provide information to clinicians and patients about what it means for their diagnosis or treatment.
Naimah: And why are there lots of different genomic tests which can be used in healthcare?
Ellen: There are different types of genetic variants, and there are tests available that are specialised for these different types of genetic variant. Some tests look at a single gene, some tests look at many genes, often known as a panel of genes. Some also compare genomic information from a patient and their parents to understand which DNA variants are likely to be important. The tests will be selected to match what is understood about the patientâs symptoms and their likely cause, and to provide the best chance of finding information which will be useful for their care.
Naimah: That was Ellen Thomas explaining genetic and genomic testing. If youâd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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Puuttuva jakso?
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Joey was diagnosed with DYRK1A syndrome at the age of 13, through the 100,000 Genomes Project. DYRK1A syndrome is a rare chromosomal disorder, caused by changes in the DYRK1A gene which causes a degree of developmental delay or learning difficulty.
In today's episode, Naimah Callachand, Head of Product Engagement and Growth at Genomics England, speaks to Joey's parents, Shaun Pye and Sarah Crawford, and Sarah Wynn, CEO of Unique, as they discuss Joey's story and how her diagnosis enabled them to connect with other parents of children with similar conditions through the charity Unique. Shaun and Sarah also discuss their role in writing the BBC television comedy drama series 'There She Goes' and how this has helped to shine a light on the rare condition community.
Unique provides support, information and networking to families affected by rare chromosome and gene disorders. For more information and support please visit the website.
You can read more about Joey's story on our website.
"Although weâre a group supporting families and patients, actually a big part of what weâre doing is around translating those complicated genetics terms, and trying to explain them to families, so they can understand the testing theyâve been offered, the results of testing, and really what the benefits and limitations of testing are...just knowing why itâs happened, being able to connect with others, being able to meet others, but actually often it doesnât necessarily change treatment."
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/Shining-a-light-on-rare-conditions.docx
Naimah: Welcome to the G Word.
[Music]
Sarah Crawford: But I would also say itâs okay to grieve the child that you didnât have that you thought you were going to have. I just think thatâs so important. And I think for me, the most difficult thing in the early couple of years was feeling like I couldnât do that because nobody appreciated that Iâd actually lost anything.
[Music]
Naimah: My name is Naimah Callachand and Iâm head of product engagement and growth at Genomics England. On todayâs episode, Iâm joined by Shaun Pye and Sarah Crawford, who are parents of Joey, who was diagnosed with DYRK1A syndrome at the age of 13, and Sarah Wynn, CEO of Unique, a charity which provides support, information and networking to families affected by rare chromosome and gene disorders. Today, Shaun and Sarah are going to share Joeyâs story, and discuss how their role in writing the BBC comedy drama There She Goes has helped to raise awareness of people with rare conditions in mainstream culture. If you enjoy todayâs episode, weâd love your support. Please like, share and rate us on wherever you listen to your podcasts.
So first of all, Shaun and Sarah, I wonder if you could tell us a bit about Joey and what sheâs like.
Shaun Pye: Yes. So, the medical stuff is that sheâs got DYRK1A syndrome, which was diagnosed a few years ago, which means that sheâs extremely learning disabled, nonverbal.
Sarah Crawford: Yeah, autistic traits.
Shaun Pye: Eating disorder, very challenging behaviour. She can be quite violent. She can be quite unpredictable. Doubly incontinent, letâs throw that in. Sheâs 17 but she obviously has a sort of childlike persona, I would say, you know. She sort of likes things that toddlers like, like toys and that sort of thing. But thatâs the medical thing. Whatâs she like, sheâs a vast mixture of different things. She can be infuriating, she can be obsessive, but she can be adorable. Occasionally, she can be very loving, especially to her mum.
Sarah Crawford: Sheâs very strong willed, you know. Once she knows she wants something, itâs impossible to shift her, isnât it? So, sheâs got a lot of self-determination [laughter].
Shaun Pye: So, her obsession at the minute, or itâs fading slightly, which is quite funny, is that sheâs become obsessed by â thereâs a toy called a Whoozit that she loves, but she became obsessed by the idea of â she was typing buggy baby Whoozit into her iPad, so thatâs how she communicates. Sheâs got quite good literacy skills.
Sarah Crawford: Yeah.
Shaun Pye: And we figured out eventually that what she wanted was she wanted her mum to take her to the park to find a buggy with a baby in it that also had a Whoozit in it that she could steal, and when Sarah explained to her at some length that it was not yours, she would say, âItâs not yours,â that drove her insane with excitement, at the idea that she could steal another childâs toy. So, itâs a good example of her because itâs funny, and, you know, it is funny, and sheâs so cheeky about it and she flaps her hands, sheâs very hand flappy, and she sort of giggles and she gets really excited, but, you know, the 2,000 time she asked to do that, and we have to walk to Mortlake Green near our house, and to the point where â again, itâs funny when it happens, but you get to the green and she doesnât even look for the buggies anymore. So, thatâs an example.
But sheâs a lot of different things, you know, and I suppose the thing that is dawning on us at the minute is that sheâs 17, sheâs going to be 18 very soon, and, you know, the list of presents that she gets on her birthday is always the same, âcos sheâs autistic. So, at Christmas, she always gets the same presents. But the idea that, for her 18th birthday, weâre going to have to buy her childrenâs toys and â you know â
Sarah Crawford: Toddlersâ toys.
Shaun Pye: Toddlersâ toys and everything, itâs sort of hitting home, but thatâs something â a bridge weâre going to cross on July 27th [laughter].
Naimah: Yeah, I can imagine thatâs quite a difficult bridge to cross, but it sounds like, you know, Joeyâs got lots of personality and you have lots of, you know, lovely times with her as well. I wanted to go back a bit before the diagnosis. So, you mentioned Joeyâs been diagnosed with DYRK1A syndrome, but can you tell me what it was like before you both â and a bit about your journey, and when you suspected maybe something might be wrong and what you did first of all.
Sarah Crawford: I mean, there were hints that things might be wrong before she was born. The measurements were such that they thought there might be intrauterine growth restriction, because basically my belly wasnât as big as it should be for dates, and that was obviously the working hypothesis. And they actually did a scan, an ultrasound quite late on in the pregnancy, which I picked up when I looked at the report was showing a small head measurement. And I remember querying it with the consultant, who said it was probably measurement artefact and nothing to worry about. But after she was born, she wouldnât latch on, you know. We had to switch to bottle feeding straight away. She was small, and the head measurement actually was small. You know, you could see on the very early one, they must have taken it kind of three times to try and get it bigger, probably angling the tape measure, and it had been crossed out and rewritten. That was the pattern. So, her head simply did not grow in those early days in the way that you would expect.
So, I was wildly anxious about this right from the get-go, and very adamant very early on that I thought that, you know, she was learning disabled. And to be fair, you know, the GP took that seriously. You know, at the six-week check-up, things werenât quite how they should be. We got in the system very early on, saw a paediatrician really quite early. So, I was, you know, fairly convinced very early. I mean, Iâm a clinical psychologist, Iâve got training in learning disability, a bit more clued into these sorts of things I guess than the general public on the whole, and I think the bigger challenge for us wasnât so much the attitude of, you know, the healthcare system. It was more trying to debate this with family, who were very much of the, âThereâs nothing wrong with her,â kind of mantra.
Shaun Pye: She wasnât our first child, so we had experience â and all children are different, but because we had that comparison â all children are different. Obviously, thereâs not a set thing. But we had a benchmark in our own minds and hearts sort of, to know that she was missing things that heâd hit, and something wasnât right. And the parental thing â basically, weâre talking about grandparents â it was sort of â there were two approaches that they took, one of which was to tell us nothing was wrong, because they couldnât bear the idea that me and Sarah were in pain or unhappy. It was just out of pure love. Itâs just a natural human reaction to say, âIâm sure everythingâs going to be alright.â They were just trying to be supportive because thatâs, you know, what they thought they should say.
And then the other approach from other members of the family was again from just a supportive, loving aspect, but it was a sort of, âThey just need a bit of tough love, pull your socks up. Lots of children are different and you just need to learn ways of dealing with it.â And the way I describe it nowadays is that theyâd mistaken Joey for someone on the far end of a spectrum of abilities or behaviours, whereas she wasnât really on that spectrum at all. She was on a different spectrum [laughter]. She wasnât a difficult child. She wasnât a naughty child, was she?
Sarah Crawford: No, no, she was a child whose brain hadnât developed.
Shaun Pye: She was a very, very different child. So, all of that has gone on over the years. And genetics wise, we had early genetics testing. Kingston Hospital took quite a lot of interest early on, and then they sort of didnât take any interest [laughter].
Sarah Crawford: No, itâs more that they ran out of technology, so they couldnât pinpoint the diagnosis with the technology they had. I mean, the geneticist was excellent, wasnât he? We really loved him.
Shaun Pye: Yeah, Sarahâs going to like this, âcos Iâm about to say I love geneticists âcos theyâre â on the spectrum of doctors, I love them, âcos one of the guys we saw just looked at it like a puzzle and he was sort of excited to solve it, and he really wanted to work out â and in a way, you could have walked away from that thinking, âWe wanted the bedside manner and we wanted the, âOh, thatâs terrible,ââ whereas he really was just a sort of â he was terribly excited about the whole thing, and he wanted to solve a Sudoku, basically, yeah. But me and Sarah walked away from that just thrilled, âcos weâre the same [laughter]. Thereâs not a Sudoku or a crossword that we donât love finishing. So, we walked away thinking, âThese are exactly the people we want involved.â
And so when I say they gave up, thatâs not fair. They just ran out of â you know, they canât spend increasing amounts of NHS money. So, they tried â you know, different genes were mentioned.
Sarah Crawford: Yeah, they tested for a whole load. I mean, his attitude was right from the get-go, you know, based on the history, everything else that had been ruled out, dysmorphic features, those kinds of things â I donât know if thatâs the terminology they would use now â but that this was going to be a chromosomal disorder, and that they would do the tests that were available, but that it was possible that those wouldnât pinpoint in, but that the technology was changing all the time, and that if they didnât find it now, they would in the future. And that was how it played out.
Shaun Pye: There was one meeting that I did get a little bit â having said that, I got slightly â but you didnât â about one of the geneticists, who sat there and said, âWeâll do this test and this test, and if they come back with any interesting things then we can get really excited.â And he used the word excited, and I was sort of a bit, âIâm not that excited by all of this.â But actually I calmed down quite quickly, and in hindsight I really wanted someone to get excited by the idea of working out â but then a long time went past. I wouldnât say that we lost interest in finding out what her genetic condition was, we didnât. Itâs just itâs something that became less and less â it wasnât like a holy grail for us. But then the opportunity came along with 100,000 Genomes, and we signed up immediately, and then they did that and it was a few years before that went through the system.
And then out of the blue really, we were asked to go and see a geneticist, and we had no idea that this is what it was. I honestly thought it was just a routine sort of, âWeâve got a few more theories,â or something, and she just said, âWeâve found out what it is.â And that moment is â well, we tried to describe it in the TV programme, but itâs quite hard to describe what goes through your mind when, after 13 and a half years, somebody suddenly says, âOh, by the way, that thing that happened with your daughter, weâve worked out what it is.â
[Music]
Naimah: I wonder if you could talk a bit about what the diagnosis meant for you both.
Shaun Pye: It was sort of different for both of us, wasnât it? I was a bit more excited, Sarah was a bit moreâŠ
Sarah Crawford: My attitude early on was that, while the label would be nice to have, it wouldnât make any material difference to anything to do â I mean, it was never going to be precise enough that it would give a map out of what weâd expect for her as an individual, and it wasnât going to change the fact that there was a severe learning disability. It wasnât going to change the challenges that we would have over things like schooling, therapies, you know, what the future holds for her. It is useful to have it, but it doesnât really change the day to day.
Shaun Pye: But what it did change, and this is where Unique is so brilliant and important, is that it puts you in touch with people who have children with a similar condition. Thatâs the main takeaway from getting the diagnosis. âCos Unique is great, and obviously in a broad sense itâs great, but to actually meet people and be in touch with people whose children have DRYK1A â so, Iâve met quite a lot of them now and Iâve met quite a few of the children. There was a meetup last year, and you just walk in and you just go, âOh my god, oh my godâ [laughter]. Literally girls running around, just the same as Joey, just the same, and the different ages as well. So, there were some in their twenties and there were some just starting out on their â whoâd only, you know, very young, been diagnosed. But just to see your life just in front of you [laughter] is very useful. So, thatâs the basic takeaway, I would say, from the diagnosis.
Naimah: Yeah. It must have been really nice to be connected with those other parents and to kind of share experiences as well.
Shaun Pye: It was, it was. And this applies to most â well, every family from Unique that Iâve ever encountered actually. Nearly all of the DYRK1A â âcos itâs spread around the world as well, so, you know, thereâs slight cultural differences, but just to see that they are all of a very similar mindset is comforting, âcos it sort of makes you think, âActually, we havenât been doing this wrong.â Itâs a sense of humour thing. Itâs an attitude to the world. Itâs the way they see their children. Itâs the way they see the outside world. Iâm not saying weâre all uniform, of course weâre not, but you can see it. When you talk to them, you can just see that they have the same sensibilities as you about the whole thing, and itâs sort of quite reassuring really that, you know, weâre not outliers.
Naimah: I just wanted to go back to, you know, when you were talking about the bit before the diagnosis, and I wanted to come to you, Sarah, to ask, you know, Shaun and Sarah both described their journey with a lot of uncertainty, but I wondered, could you tell me a bit more about the role Unique plays in this part of the journey for parents?
Sarah Wynn: Yes. Well, actually I think Shaunâs done such a good job of summing up why Unique exists already, thank you, Shaun. But I think really what weâre aiming to do is to try to alleviate that sense of helplessness and being overwhelmed, and isolation that often families feel when they have a child thatâs got additional needs. I think our experience with our Unique community is very similar to that that Shaun and Sarah have described. So, many parents know that there is something â that their child isnât developing as they would expect. And we hear lots and lots of stories of families going to healthcare professionals and actually not being taken seriously, or like Shaun and Sarah were saying, you know, everybody saying, âNo, theyâre just a bit delayed, it will all be fine.â And so I think thatâs a common experience of many families, that the parents inherently understand and know their child better than everyone else, and itâs very common that families have to wait quite a long time to get to that point where they get to a diagnosis.
And often I think the uncertainty continues after you get that diagnosis, because as Shaun and Sarah said, you get a diagnosis of a rare condition and actually there just isnât that much information available. So at Unique, we try to help in various ways. One is by connecting families with other families, and that might be other families whoâve got the same condition, but it might also be families who are just going through the same experiences as you are, so youâve got someone to share your journey with. And the other thing we try to do is to help families understand the kinds of genetic testing theyâve been offered, and a bit about the results of genetic testing. Because of course genetics is something that lots of people havenât thought about since school, and actually quite often hoped they never had to think about again.
Although weâre a group supporting families and patients, actually a big part of what weâre doing is around translating those complicated genetics terms, and trying to explain them to families, so they can understand the testing theyâve been offered, the results of testing, and really what the benefits and limitations of testing are. Sarah said, often you get a result and a diagnosis from genetic testing, but that doesnât give you a magic treatment thatâs going to cure your child. Itâs really important, for all the reasons Shaun and Sarah have already said, just knowing why itâs happened, being able to connect with others, being able to meet others, but actually often it doesnât necessarily change treatment.
Shaun Pye: I guess one thing I would say, just âcos it was important to us, and itâs de novo in our case, but thatâs comforting to know. We always suspected it was and we were always told it was, but to have that confirmed means â I mean, weâre not going to have anymore children, but itâs more to do with our son and whether thereâs something inherent that could be passed on.
Sarah Wynn: Yeah, it gives you information that you can use for either your own family planning or other family members.
Naimah: You mentioned that Joey received her diagnosis via the 100,000 Genomes Project. How did that come about?
Sarah Crawford: I think it was offered, as in the 100,000 Genomes Project was the only way that that was potentially available at the time, that this was effectively a project that was going on to try to answer those unanswerable questions with the technology they had at the time. I mean, it was years between us enrolling in it and getting the answer.
Shaun Pye: Itâs so important to me in hindsight the diagnosis, just for all the reasons that weâve been discussing, but without doing down the role of genetics, there was a period of Joeyâs life when we thought weâd run out of road with the testing, and it wasnât something that really I was obsessed with or occupied my mind massively. It wasnât like me and Sarah were saying, âWe must get back to Kingston Hospital. We must get back to the geneticists. We must write to the NHS. We must insist that they do this.â Weâd sort of resigned ourselves to the fact that theyâd done all that they could and they hadnât found it, and thatâs what it was going to be. Having said that, when 100,000 came along, we obviously jumped at the chance. We had no misgivings about it whatsoever, âcos I think weâd resigned ourselves to the fact that we might never know.
Sarah Crawford: I think I thought that at some point we would, because the technology, the methodology that theyâre using obviously was changing all the time, but it didnât preoccupy me because I didnât think it would make a massive amount of difference. It probably made a bit more difference than I thought it would, for the reasons that Shaun and Sarah have said, about, you know, particularly the sort of connecting with others, you know, just realising how useful it is to be able to hear about the similarities and differences that other families experience.
Shaun Pye: I think a key point for us, and Iâm sure this is true for the vast majority of Unique families, that we never thought that there was a cure. We never ever, ever, ever, ever, ever thought there was. And nobody in our family did. Itâs not like anyone was saying, âOh, with this treatment or that treatmentâŠâ Once you know that itâs DYRK1A, thereâs obviously things that you can tailor towards her in terms of therapy, you know, there are things that you can do, but we were never under the illusion that if we found out what it was, she could go on and some sort of drug would suddenly make it better.
Sarah Crawford: Yeah, weâre not queuing up for experimental stem cell treatment [laughter] in weird and wonderful parts of the world, you know. Whatâs happened has happened. Her brain didnât develop properly in utero and beyond. There is no changing that.
Naimah: But I guess with diagnosis, and like you said, if you can get some relief from some of those other symptoms that are caused by it, then, you know, thatâs some sort of relief for Joey and a bit of help.
Shaun Pye: Yeah, there are absolutely concrete things that you can learn that will â Joey will never be better, but talking to the other families â eating disorder, thatâs one of them. Constipation, thatâs another thing. But hearing their experiences, hearing the roads theyâve gone down, finding out that thereâs, you know, a unit somewhere in the country that specialises in this, that or the other, these are concrete things. Itâs not just about emotional support. Itâs absolutely about practical support. But thereâs no magic wand, but there are things that, you know, weâve learnt that can help.
Naimah: And then Sarah, to come to you then, do you find that families find it difficult to seek out help from Unique once theyâve received a diagnosis, or are they likely to come quite quickly to you? Whatâs your experience?
Sarah Wynn: Itâs a really good question, and of course we donât know the ones that never find their way to us. But what we try to do at Unique is to be sort of warm and friendly and welcoming, so that itâs not too daunting. âCos I think all of these things are an extra thing for parents who are already busy and dealing with lots of medical appointments and therapies, so we try to make it as easy as possible to join us. Many, many families do join us at that point of diagnosis, because thatâs when theyâre looking for more information. Actually, you can get in touch with Unique and if you decided you didnât want to join us, thatâs also fine. So, we have a helpline that you can call. And for some people, joining a support group just isnât their cup of tea, and thatâs really fine. Other people find us a little bit later on, you know, perhaps when their child starts school or, you know, thereâs sorts of crunch points where people are looking for extra information or support that they tend to find their way to us.
But one of the things we try really hard to do is to get the word out that organisations like ours exist, so that we can be contacted if people want to. And lots of our families come, like Shaun and Sarah, after the geneticist has told them that weâre there. So, thatâs a really important thing for us is that everybody knows weâre there. You can join us and involve yourself as much or as little as you want. So, as weâve already talked about, one of the things we do is put families in touch with each other, but not all families want that. So, you know, you can join and remain no contact, and stay quietly under the radar if youâd like to. But those people often want their child to be sort of counted in the system, you know. When you say how x number of people have DYRK1A, they want their child to be in that number even if they donât want to go to the meetups, or theyâre not quite ready to do that. And of course people change. So, some people join us and think, âWeâre just going to quietly sit here for a bit,â and then change their mind a bit further down the line.
I think, although There She Goes, and what Sarah and Shaun have said about their journey is really similar to many peopleâs journeys, of course everyone is a bit different, and so people want different things at different times. And what we try to do at Unique is to be those things for whenever families need us.
Naimah: Yeah, that must be really reassuring for families, knowing that they can come to you whenever they feel ready to more than anything.
Shaun Pye: Just to jump in quickly as a sort of user of Unique, from the sort of different perspective from Sarah, that is literally how the service presents. Thatâs not an ideal that they aspire to. Thatâs what itâs like. So, I can confirm that â I mean, people think different things, and within our DYRK1A group, for example, you know, thereâs a broad range of people who think various things, but the one thing about it and Unique is itâs very well self-policed, so people know how to behave. You wonât be subjected to ill informed sort of medical nonsense. Itâs very well self-policed, but itâs also very, very occasionally â Iâm speaking for the DYRK1A group â the example they gave me was around covid and vaccinations, and, you know, people have very strong views about it, and these forums arenât the places to be having that sort of discussion.
Sarah Wynn: I think thatâs exactly it. One of the ways families can connect with each other is via an online forum, and generally we take quite a light touch in moderating it, because the forum is for the families, and we want them to feel ownership and that itâs their safe space. But yeah, ever so occasionally, it needs just a tiny little bit of input. But yeah, I think Shaunâs right, everybodyâs there for the same reason, and thatâs to kind of share experiences, sometimes vent about the world, ask questions, and actually celebrate things that other people might not see as such a celebration. You know, lots of our families, their children might be late to walk, and itâs a place where you can celebrate all of those sorts of things as well.
[Music]
Naimah: So, next I want to move on to talk about 'There She Goes'. So, you mentioned it briefly there, Sarah. So, this is the BBC Two comedy drama, for which Shaun and Sarah were both writers on, and it really draws upon your real-life experiences of caring for Joey. And although the series is posed as a gentle comedy, it also displays really frank and honest emotions experienced by Emily and Simon, who are the parents of Rosie in the programme. Letâs listen to the poignant clip from the series by Jessica Hynes, who plays the mother, Emily.
Emily: You know, when youâre younger and daydream about what family you might have â so, I was the girl who thought Claire always got away with murder. Or when we found out Ben was going to be a boy, if it would be like you and Soph, you know, dorky older brother, biffy outdoor sister who everyone liked, you know. But in none of my dreams was there a girl who⊠Yeah, who was like Rosie. Yeah⊠No one ever dreams of a child like Rosie⊠You know, and I⊠I love Rosie, but why do I have to be defined by her? You know, for a long time, I felt cheated by her, because she wasnât the girl that I dreamt about, you know. Sheâd taken her place. And then as she got older and I accepted her more, you know, what if it wasnât that sheâd taken her place, what if she just pushed in the queue and then if we started again, then if I had, you know, a normal girl, and then I wouldnât have to⊠I wouldnât have to resent Rosie anymore because Iâd have the family that Iâd always wanted, and Iâd have â Iâd have Rosie as well, yeah. [Sobbing] Just after all these years, havenât I earnt that?
[Music]
Naimah: Off the back of that, I wondered if you could both tell me a bit more about what it meant for you being able to write for the programme and, you know, what itâs meant in the aftermath as well.
Shaun Pye: So, it came about - I basically am a TV writer and Sarahâs a psychologist, but it came about primarily because I was trying to think of something to write about and we realised that Joeyâs just an incredible character. Those sort of children arenât featured on mainstream television really at all, I would say. And so we thought it would be an interesting thing to do. But from that sort of slightly selfish motive, I wrote an episode, and Sarah read it and said, âYouâre not doing that, itâs not honest enoughâ [laughter]. So, Sarah came on board as a writer with me and we cowrote it. The whole thingâs cowritten. And itâs the most important piece of work Iâve ever done, I ever will do, and it became far more than just a TV programme.
The first series went out and we had a screening, and Unique came to the screening, along with some of the other charities, and we were so terrified of what the response would be. And the fact that the response was what it was, which was overwhelmingly, âItâs like looking at our own lives on television,â it was recognition. It was nothing to do with whether the stupid jokes were funny or anything [laughter]. It was purely whether â if anyone had turned round and said, âThis has got nothing to do with what itâs like bringing up our child,â or our brother or sister or whatever, that would have been quite bad for us, but it wasnât, and thatâs been the overwhelming response since. Itâs, âThank you for putting our life on television, âcos itâs not normally on television.â
So, it became that, and so the second series was even more about that, and then the special that we did was almost totally aimed at, we need to tell these stories because there are so many people in this country who this story isnât being told for them. And it so happened that Joey hit puberty and had some very, very, very problematic behaviours, sort of self-harming behaviours, it happened quite close to her being diagnosed, so we thought this story is just written for us. Joeyâs written it for us. So, we just sort of wrote down what happened. That was sort of what it was. And then obviously the response to that was very good. So yeah, and we wanted to feature Unique âcos that was such an important part of what weâd been through.
So yeah, it went from me wanting to further my career to that having nothing to do with it, and me wanting to [laughter] tell the story of children with rare chromosomal disorders and learning disability, and thatâs what it became.
Naimah: Iâm sure it must have been almost quite cathartic, I imagine, in a way, to share your story that way, and also, you know, give you a real sense of accomplishment to be able to kind of share your story on that platform. Like you said, like itâs never been done before in such a way, and to get that kind of response from other families, it must have really just helped you both in your journey as well, I can imagine.
Shaun Pye: For me, because itâs what I do for a living, it still retained a certain sense of my job. And, you know, emotionally, obviously, entirely committed to it. All the bits that make you sort of cry, or all the bits that are like, oh my god, Sarah wrote â I wrote all the stupid bits that David Tennant says [laughter]. So, I think it was more cathartic for you. You really had to dig deep into some quite unpleasant memories [laughter].
Sarah Crawford: Yeah, it wasnât always the most comfortable process, you know. Weâd sort of agree â I mean, particularly in the earlier process, weâd sort of have a little think about what we wanted to talk about, and then Iâd go off and like kind of delve deep into memory, and just type a stream of consciousness, and Iâd be sitting there sobbing [laughter], you know, with tears rolling down my face, you know, just reliving these really awful experiences. But yeah, I think the end process ended up being cathartic, and a lot of that was stuff that I would never have imagined sharing with anybody [laughter], let alone, you know, this huge audience of people, which â yeah, strange how things evolve.
Shaun Pye: Yeah, I think possibly if we hadnât done this then we might have just tried to not think about these things and not bring them back, and I think we probably wouldnât have spoken to each other â we may have, I donât know. I donât know what would have happened. But I donât think these things would have come out into the open. And very interestingly, another side aspect of it in the catharsis way is the effect the programme had on the wider family. There were certain members of the family who were really shaken by that programme, really shaken, because they had a set view. Even as Joey got older, they had a set view of the history and what had happened, and they were really shaken by the idea that their â out of love again, thereâs nothing bad here, but they were really shaken by the idea that their actions had a detrimental effect on us when Joey was born.
You know, there were people saying, âWell, I didnât say that there was nothing wrong with her,â and, âI didnât say this or that,â but actually when you see it presented in the programme then there was a lot of re-evaluation that went on, in a good way, in a positive way and itâs all good.
Sarah Crawford: I think thereâs something about seeing it, you know, and especially given, you know, we were so fortunate with the cast because theyâre so good at portraying it. And I think thereâs a power in seeing things played out rather than just hearing about them in the abstract.
Naimah: Yeah, definitely. I definitely had moments of crying and laughing, and a range of emotions while I was watching it, so yeah, definitely very powerful. And I guess itâs really great for other families going through similar circumstances, for their families to see whatâs happening and, you know, thereâs a lot that can be learned from the programme as well. So, you know, itâs, yeah, really a powerful piece that you put together.
Sarah Wynn: I would really like to echo that. I think Shaun and Sarah have said before that they didnât do it to represent everybodyâs experience, but actually that is exactly what it has provided. I would say that huge numbers of people are really grateful that that portrayal is there, so that they can be seen and heard and understood so brilliantly. But it has provided other families with the opportunity to show it to their friends and family, so that they understand their life as well. And so I think itâs had a hugely positive reaction from our Unique community. And I think itâs not always an easy watch, I think lots of families would say itâs challenging to see it up close in front of you, but I think itâs really cathartic and has been just incredibly powerful at showing these sorts of stories, which, as you said, just donât get shown very often.
And I think particularly when we think that rare conditions, although theyâre individually rare, if you put all of the rare chromosome conditions together, theyâre not actually that rare, so these are stories that are going on up and down the country and all over the world.
Shaun Pye: Just to follow up on something Sarah said earlier on about, you can take as much or little as you like from Unique, itâs the same with the show. Iâve had lots of people get in touch with me or talk to me in person and say, âIâm really sorry, I tried to watch âThere She Goesâ and I canât watch it,â and I have to say, âDonât apologise, you have nothing to apologise for. You take what you need from it. If you canât watch it then donât watch it. If you can watch it then do. There is literally no right or wrong way of doing this. There really isnât.â But having said that, the nicest comment â well, one of the nicest comments Iâve seen was on the DYRK1A forum. It was someone who casually referred to it as âour show,â as in the DYRK1A community, it belongs to them, and that â yeah, a little tear, a little tear went down my face [laughter].
Naimah: Yeah, that must have been a lovely thing for you to read. Thatâs really nice.
Sarah Wynn: Also from the Unique and general people who have rare conditions community, itâs been so fantastic for raising awareness about genetic testing and rare conditions in general, and, you know, there just isnât â because these stories donât get talked about or shown about very often, itâs been really great from that point of view as well.
Naimah: And hopefully this will be the catalyst for similar programmes and, you know, more things in the mainstream media as well. And you did touch on it briefly there, Sarah, about, you know, what the programmeâs meant for Unique, you know, and the Unique community being very supportive, but have more people reached out to Unique since the programme?
Sarah Wynn: I think the main takeaway is that being heard, âOur familyâs being heard and represented,â which I think is really important. But yes, weâve got lots and lots of new families that have come to us through watching There She Goes. And it was really fortuitous that when the special aired last spring/summer, it was the evening before our awareness day, which I think was a complete coincidence but actually turned out to be really great timing. So, we got lots and lots of new families get in touch with us, many of whom then went on to join us. But actually what it also did was get lots of members whoâd been members for a long time but perhaps had been a bit quiet, or hadnât been in touch, so it sort of also reinvigorated that engagement from other members who we might not have heard about for ages, and who might have got older children and had been in touch at the point when they were diagnosed, and then hadnât been.
So, it has just been such a brilliant, brilliant experience to have Unique as part of it. And I think thatâs really important. At Unique, we have members from 120 different countries, and the reason is that when you have these rare conditions, youâre really unlikely to find someone in the same town as you, possibly not even the same country with some rare conditions, and so the idea that you can connect with people all over the world I think is really important, particularly in rare conditions.
Naimah: Yeah, thatâs great, and hopefully, you know, it just continues to increase support with Unique and, you know, families know they can still come to you as a resource and as that continues. So, I just wanted to kind of wrap up here and come to the final question. So, you know, your story highlights a lot of challenges, a lot of difficulties, a lot of ups and downs, but I just wondered, Shaun and Sarah, if you had any advice for other parents going through similar circumstances.
Shaun Pye: Yeah, I think one of the things is what I just said, which is I would tell people thereâs no right or wrong way of doing this. I would say, from my experience, donât be hard on yourself, and youâre going to think that you wish it never happened to you and thatâs fine. That is absolutely fine. Thatâs normal. Weâve all thought that. It doesnât make you a bad parent. It makes you a normal human being. I would say to get in touch with Unique. I shied away a little bit from help and charities, âcos I think it was a sort of pride. I think I had a preconception that it would be glass half full, put on a happy smile, best foot forward, blitz spirit sort of. We have encountered it a little bit over the years, not very much, but weâve encountered a little bit of, you know, âAs long as you love them, thatâs the most important thing,â and, you know, which is fine and that is an okay perspective to have, but there are times when itâs just not what you want to hear. I want to be allowed to feel the feelings that Iâm having without feeling guilty.
So, I would encourage people to seek support from Unique or from wherever. But, you know, generally, the thing Iâve learnt about people is that the vast, vast majority of people are nice and kind and understanding about this. Not everyone, but most people are good people and, you know, people should remember that, I think.
Sarah Crawford: Yeah. I mean, the first thing I was going to say in terms of advice to other people was something Shaun said already, which is the donât be harsh on yourself, because, you know, youâre allowed to find it difficult. But I would also say itâs okay to grieve the child that you didnât have that you thought you were going to have. I just think thatâs so important. And I think for me, the most difficult thing in the early couple of years was feeling like I couldnât do that because nobody appreciated that Iâd actually lost anything. The world seems to use the word difference a lot at the minute, you know, âThese children are different, theyâre differently abled,â but actually it is disability [laughter], and it is more difficult, you know.
There are rewards, there are positives, but, you know, sheâs 17 and a half now, our daughter. When our son was 17 and a half, you know, the challenges were different, but they were also nowhere near as big [laughter], and I donât think that should get lost. Because I think parents need to feel itâs okay to get the help they need and to push for the help they need, and not feel like theyâve just got to kind of put on a brave face and, you know, as Shaun was saying, the attitude sometimes of, âWell, youâve just got to get on with it.â Because while you do, actually, you know, you do need help to do that. It is difficult.
Shaun Pye: The only other thing Iâd say is, just âcos Sarah just mentioned it and it gets forgotten, is the siblings thing. The families with Unique will have all manner of different configurations. I can only speak from our own experience, but Joey has an elder brother, Frank, who is, well, in my opinion, the best human being in the world [laughter], and Iâm sure in his motherâs opinion as well, but my experience, never forget about the toll it takes on siblings. âCos Frank is a very, very loving brother. Only last night, Joey was typing, âFrank book.â âCos heâs gone to university, she likes looking at pictures of him in the photo albums. She likes looking at pictures of old toys mainly.
Sarah Crawford: Yeah, yeah, she likes looking at her as a baby and the toys they had.
Shaun Pye: Yeah, but itâs not really advice, itâs just, you know, thereâs a danger that Joey could have taken over our entire family life, and especially Sarah made sure that didnât happen and that, you know, we were a unit and he was â but, you know, it is possible that it can swallow up your entire life.
[Music]
Naimah: Okay, so weâll wrap the interview up there. Thank you so much to our guests, Shaun Pye, Sarah Crawford and Sarah Wynn for joining us today as we discussed Shaun and Sarahâs journey to Joeyâs diagnosis, and how charities like Unique can support families of those living with rare conditions. If youâd like to hear more like this, please subscribe to the G Word on your favourite podcast app. Thank you for listening. Iâve been your host and producer, Naimah Callachand, and this podcast was edited by Bill Griffin at Ventoux Digital.
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In this explainer episode, weâve asked Clare Kennedy, Clinical Bioinformatician at Genomics England, to explain what the difference is between DNA and RNA, in less than 10 minutes.
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 youâve got any questions, or have any other topics youâd like us to explain, feel free to contact us on [email protected].
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/004-What-is-the-difference-between-DNA-and-RNA.docx
Naimah: What is the difference between DNA and RNA? Today, Iâm joined by Clare Kennedy, whoâs a Clinical Bioinformatician here at Genomics England, whoâs going to tell us more.
So first of all, Clare, what is DNA?
Clare: So, DNA stands for deoxyribonucleic acid, and although this is quite a mouthful, DNA is essentially an instruction manual for our body on how to function, and a copy of this manual is stored within almost every cell of the body in a structure called the nucleus. So, our DNA essentially comprises all of the genetic information we inherit from our parents, and this information is contained within two long strands of code, and we inherit one strand of code from our mother and one from our father, and both strands combine and they form a twisted ladder like structure that we call the DNA double helix. So, each strand is made up of small units called nucleotides, and these nucleotides, they differ based on their chemical composition. They can either contain a molecule of adenine, guanine, cytosine or thiamine, and this is why we often see our DNA sequence represented by the letters A, G, C or T. And in total, our entire DNA sequence consists of three billion of these nucleotides.
So, as this DNA instruction manual is quite long, it needs to be broken up into smaller sections that the body can read, and thatâs where genes come in. So, a gene is a segment of the DNA and it contains a particular set of instructions, normally on how to make a protein. So, proteins are essential for life and theyâre involved in almost every process within our body, and that is why we have around 20,000 protein coding genes in our DNA.
Naimah: So then can you tell me, what is RNA and how does this differ from DNA?
Clare: So, like DNA, RNA, which stands for ribonucleic acid, is an incredibly important molecule that encodes genetic information, and itâs found in all cells of the body. So, RNA consists of only a single strand of nucleotide units, and just like DNA, RNA can be represented by four letters that reflect the chemical composition of each nucleotide. These four letters do differ slightly though, because RNA contains uracil instead of thiamine, so you can distinguish a DNA sequence from an RNA sequence by the presence of the letter U and the absence of the letter T. So, while we think of the DNA as the instruction manual for the body that contains all of our genetic code, RNA is the reader of this instruction manual, and it helps the cell to carry out these instructions, so the proteins can be made.
Naimah: So, can you tell me a bit more about this protein production, and how are DNA and RNA involved?
Clare: So, protein production all starts in the nucleus with the DNA. So, if we want to make protein, we must first read the portion of the DNA or the gene that contains the instructions to make this protein. So, because DNA is so long, itâs really tightly packed into our nucleus, and the
region weâre interested in might not be accessible, so we first need to open this region out. So, molecules and enzymes help us open this region of the DNA, and once the gene is accessible, they start to read it, and they start to transcribe the instructions that are encoded within the gene into a type of RNA called messenger RNA. So, as the name suggests, messenger RNA is the communicator of the instructions contained within our DNA, and this process is called transcription.
So, the messenger RNA then leaves the nucleus and enters the main body of our cell, which is called the cytoplasm, and messenger RNA is transported to the ribosome. Now, the ribosome is a piece of machinery which will build the protein, and itâll use the instructions that are encoded by the messenger RNA. But we need materials to build the protein, and thatâs where a type of RNA called transfer RNA comes in. So, transfer RNA is instructed to hunt down the building blocks or the amino acids that we need to build the protein, and it brings these back to the ribosome. And then we have a third type of RNA that gets involved called ribosomal RNA. So, ribosomal RNA helps the ribosome assemble these amino acids into proteins in a process known as translation.
So, it really is a group effort between the messenger RNA, the transfer RNA and the ribosomal RNA. And once the protein has been assembled, it might go through some more processing steps, and itâs eventually exported by the cell to where itâs needed.
Naimah: Okay, so apart from their roles, are there other key differences between DNA and RNA?
Clare: So, as we touched on earlier, the main difference between DNA and RNA is in their structure. So, we have, DNA is in a double stranded helical structure, whereas RNA is single stranded. And because of DNA having this double standard helical structure, itâs actually much more stable than RNA, which is more susceptible to degradation by enzymes and other molecules. As DNA contains our genetic code, itâs much longer than RNA, and you can only find DNA in the nucleus of the cell as itâs much too large to leave the nucleus, whereas you can see RNA in the nucleus and in the cytoplasm. RNA and DNA also differ in the type of code or the lettering they use, so they both use the A, G and C letters in their code, while DNAâs is the T lettering and RNAâs is the U lettering, and this is due to the differences in the chemical compositions of the nucleotides that make up DNA and RNA.
And the nucleotides in DNA also contain different types of sugars from the nucleotides used in RNAs. So, in DNAs, you would have a deoxyribose sugar, whereas an RNA uses a ribose sugar. Thatâs where we get the deoxyribonucleic acid and the ribonucleic acid.
Naimah: So Clare, weâve talked about the difference between DNA and RNA, but why are these important in clinical care?
Clare: So, we can use DNA and RNA to diagnose illness and to also develop therapies against these illnesses.
Naimah: Can you give me some examples of where DNA and RNA are used for diagnosing conditions?
Clare: Absolutely, so an excellent example is in the diagnosis of cancer. So, the majority of cancers are caused by mistakes in the genetic information encoded within our DNA, and result in the production of malformed proteins. So, we can normally look at the DNA and we can identify certain genetic mutations that cause the cancer. So, examples are breast cancer, ovarian cancers, lung cancers, essentially all types of cancers that you can think of will have genetic mutations associated with them. But then there are cases where no problem with the DNA can be identified, but then when we look at the RNA, we do see a problem. So, a particular example was recently shown in breast and ovarian cancer, where a gene that encodes for a protein called BRCA1 was not shown to have any genetic mutations, however when we looked at the RNA produced from that gene, we could see there are problems with that RNA and essentially identify a genetic cause for that cancer.
Naimah: Could you also give me any examples of where RNA or DNA are being used in therapies?
Clare: So, absolutely. So, most of us will have heard of RNA vaccines in recent times, such as those that were generated against COVID-19. And essentially how these vaccines work is they deliver small messenger RNA from the virus into the body. The body can then make a protein from this messenger RNA, and the immune system recognises this as an invader and destroys it. So, this low level of viral exposure essentially trains your immune system to respond in the event of an infection, and really the success of the MRNA vaccines against covid has really paved the way for the use of MRNA vaccines against cancer. So, itâs believed that we can stimulate an immune response that would destroy a cancer cell using MRNA vaccines, and there are now some studies that are looking at developing messenger RNA vaccines against cervical cancer in particular.
So, DNA therapies can actually target genetic mutations and correct them to prevent illness, and one such example is a gene editing treatment that has been developed for the treatment of blood disorders, such as sickle cell anaemia.
Naimah: That was Clare Kennedy explaining the difference between DNA and RNA. If youâd like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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There are a range of outcomes from a genomic test. The results might provide a diagnosis, there may be a variant of uncertain significance, where a genetic variant is likely the cause of the condition, or there might be no particular gene found that is linked to the phenotype or clinical condition - also known as a "no primary finding" result. In this episode, our guests explore the impact of a "no primary finding" result on families, discussing the common experiences and expectations of parents and patients who undergo that genetic testing, and the role that hope plays in the experiences of children with rare and undiagnosed conditions.
Today's host, Lisa Beaton, member of the Participant Panel at Genomics England is joined by Dr Celine Lewis, Principal Research Fellow in Genomics at UCL, Great Ormond Street Institute of Child Health, Jana Gurasashvili, a Genetic Counsellor, and Louise Fish, CEO of Genetic Alliance.
"I think itâs also really important to add that hope isnât necessarily lost when you donât get a diagnostic result. And in a sense, what can be really helpful is for genetic counsellors to reframe that hope...sort of giving it a different context."
For more information on the SWAN UK project which supports families with children that have been through genetic testing but have not found a result following that genetic testing, visit the website.Read more about the study by Jana Gurasashvili and Dr Celine Lewis: The disequilibrium of hope: a grounded theory analysis of parents' experiences of receiving a "no primary finding" result from genome sequencing.You can read the transcript below or down it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/Hope-for-those-with-no-primary-findings.docx
Lisa: Hello, welcome to the G Word.
Lisa: I think in the back of my mind, subconsciously, I had hoped that when we eventually got a diagnosis, it would â I donât know, bells and whistles, balloons going off, fireworks, etc. And then the experience of a letter thumping on the doormat, and I recognised the postmark quite quickly, and it was at that moment I suddenly thought, âOh gosh, I havenât buried all these feelings of hope.â Because I opened that letter with quite trembly hands, and then this diagnosis or lack of diagnosis, you know, nothing had been found, and it was a bit⊠I donât know if itâs been described as like a nail in the coffin experience, because I really hadnât realised I was still clinging to this hope all that time, and then again it was, you know, another, âNo, nothingâs there.
Lisa: My name is Lisa Beaton and Iâm a member of the participant panel at Genomics England. On todayâs episode, Iâm joined by Dr Celine Lewis, the principal research fellow in Genomics at UCL, Great Ormond Street Institute of Child Health, Jana Gurasashvili, a genetic counsellor, and Louise Fish, the CEO of Genetic Alliance. Today weâll be discussing the impact on parents with children with rare conditions, who received a no primary findings result after diagnostic whole genome sequencing. If you enjoy todayâs episode, weâd love your support. Please like, share and rate us on wherever you listen to your podcasts.
Can I ask all of us here present to introduce themselves, please?
Celine: Hi everyone, Iâm Celine, Iâm a behavioural scientist in genomics at UCL Institute of Child Health, and I currently hold an NAHR advanced fellowship to look at the implementation of WGS, or whole genome sequencing, in the NHS.
Jana: Iâm Jana Gurasashvili and Iâm a genetic counsellor at Northwest Thames Regional Genetic Service, and prior to that I was at Great Ormond Street, involved with consenting families to the 100,000 Genomes Project, and I also have an ongoing interest in the lived experience of patients and parents of genetic counselling and rare disease.
Louise: Hi, Iâm Louise Fish, Iâm the chief executive of Genetic Alliance UK, and we are an alliance of around 230 charities and support groups that work with patients and families who have particular rare conditions. We also run a really longstanding project called SWAN UK, and SWAN stands for syndromes without a name. And the SWAN UK project supports families with children that have been through genetic testing but have not found a result following that genetic testing. So, itâs clear they have a genetic condition, but science hasnât quite advanced far enough yet to tell us what that means and what that will mean for their child, and what that will mean for their family over the coming years.
Lisa: And I personally can attest to the wonderful support that SWAN UK can offer because, as the parent of a still undiagnosed child, I have been involved myself with SWAN UK since my daughter was around the age of three to four years old. Itâs brilliant being a part of my big SWAN UK family. We first realised that there were some â I suppose something wrong with our daughter when she was around two weeks of age, but it wasnât something I could specifically put my finger on. I couldnât at that point have taken her to a doctor and said, âI donât know whatâs wrong but thereâs something wrong.â I just knew in my heart of hearts, probably because I have three elder children, that there were issues, and things werenât developing as they should. She cried a lot, she screamed a lot, she never seemed to be comfortable in any position when you held her, when she was asleep, when she was upright. It didnât seem to matter what you did, she was just a rigid, stuck child, for want of a better word. And all my mum senses were screaming, but it completely sounded ridiculous to take her to a doctor saying, âShe feels wrong.â
And I think thatâs quite a SWAN UK experience, from chatting to other families with similar situations. The parents just know that thereâs something not right, but it can be very isolating not to be able to identify kind of where that starts and what it is. In our case, it wasnât until our daughter was nine weeks old that things became much more obvious, that there were developmental concerns physically and medically, and at that point we went from my sort of mutterings that there was something wrong but I wasnât sure what it was, to a sudden hospital admission with quite a shocking turn of events. From something that had started out quite normally, as a routine visit to the baby clinic, to suddenly being seen by a troop of different paediatricians, and doctors coming in and out constantly, asking different questions, and sending us off all over the building for different tests and x-rays and imaging. And being given a partial diagnosis that our daughter had a condition called arthrogryposis, but it was clear that there was much more going on than that, and we would need referring to many more different fields. And that day really our diagnostic odyssey, for want of a better word, began.
So actually, in terms of that diagnostic odyssey, many parents of children with rare undiagnosed conditions experience this, and when we agree to have genetic testing, we feel that we are going to get these answers straight away, and that every appointment that you go along to is going to be the one that brings you the answers. But certainly in our experience kind of 15 years on, thatâs not been the story at all. Celine, can I ask you to explain what the words no primary findings actually mean when a parent receives that regarding their child?
Celine: So, thereâs a range of different possible outcomes from a genomic test. So, the results might provide a diagnosis to that patient and family, or other situations, there might be a variant of uncertain significance, so we donât necessarily know if the gene that we found, a genetic variant is the likely cause of the condition, or we might find no particular gene at all that we think is linked to the childâs phenotype or clinical condition. So, thatâs what we mean really when weâre sort of saying no primary finding.
Lisa: Louise, would you be kind enough to explain what you think the impact of no primary findings means to families like my own, parents who donât have a genetic likelihood cause, just a gene thrown up to diagnose their child?
Louise: Yeah, I think itâs a huge challenge for families, and youâll obviously know that from your own experience. People go to have genetic testing hoping it will give them some answers, first and foremost, just to kind of understand, you know, what condition their child has and what the likely impact thatâs going to be on their child and on the childâs life, and on the familyâs wider life. And I think one of the things that we really ask genetic counsellors and geneticists to do is help people understand before the genetic testing takes place that there may be nothing found from it, so that that kind of expectation is built in. Because people hope that they will get a diagnosis that will give them answers about what the impact of the condition will be on their lives. In a best-case scenario, access to a particular treatment that might be a huge help for their child, but at the very least, access to a range of services and support for their child. So, that kind of diagnosis is often seen by families as the key to unlocking a range of services and support that will help them and their families at what is the beginning of a lifelong journey.
And I think when families get no diagnosis, thereâs a real concern on behalf of families, a, that they donât understand how their childâs going to be affected by the condition. What weâre really careful to say to families is, âJust âcos you donât have a diagnosis with a name, your child is still the same person they were before. They still have exactly the same bundle of needs as they had before, and you will still need to work with the NHS and with wider services to make sure that they can access speech and language therapy, and physiotherapy, and all of the services that they are going to need and you are going to need to help them live their lives to the full.â But I think that moment of not getting a diagnosis is when people feel I think real â the uncertainty continues, and uncertainty, we know, is a really hard thing to live with, and the lack of clarity about which services youâll be able to access. So, I think psychologically itâs a massive impact on the family not to have the answers that they were looking for, or the key to the services that they were hoping would be there.
Lisa: Thank you, Louise, yeah, I would definitely agree with that. We had a no primary findings result in I think it was 2019. It was a really bittersweet moment because my daughterâs list of various different conditions kind of â by this point, named parts of difficulties for her spans over sort of two pages of A4, and yet on the letter back from the genomics service, it just says that, you know, nothing causative has been found. And so part of you is left wondering, well, how can there be all these different conditions or difficulties, and yet thereâs still nothing there? And I know personally, I had comments when she was much younger, every time a test came back, where people would say things like, âOh well, thatâs great news,â and to some extent it was great news that something hadnât been found, but also if that hadnât been found, what was still out there? And that fear of kind of the unknown was extremely difficult.
And also paradoxically, there was a sense of some very well meaning people saying things like, âOh well, if they havenât found anything then there canât be too much wrong.â But yeah, I have a child who is tube fed and on multiple different medications, and cared for basically for 24 hours a day, so that doesnât really fit in with the picture of there not being very much wrong from a personal perspective. And I think it can make you as a parent/carer feel perhaps thereâs a tendency to downplay that there is an issue and that perhaps, you know, youâre making it up, for want of a better word, and that sense of isolation around that can certainly be problematic. Celine, if I can come to you, that diagnostic odyssey, what are the common experiences and expectations of parents and patients who undergo that genetic testing from your perspective?
Celine: Well, I think sort of parents go into genetics testing for a whole range of reasons really, and Louise has already alluded to many of these. Ones that Iâve come across in my own work include wanting to know why their child has a particular health problem, so that that child can access the most suitable treatments or therapies, or even access clinical trials. Even relief from guilt for many parents, a validation that the parents hadnât done anything wrong during their pregnancy to cause the childâs condition, and thatâs hugely important really, to try and get that relief from guilt. Also to know whether future children might be affected by the same condition, and then more social reasons really, for example, making contact with other parents through support groups, or access to social and educational support.
And I think thereâs also a drive from many parents to feel that theyâre doing everything absolutely possible for their child. I mean, particularly with something like the 100,000 Genomes Project, it was really a sort of first of its kind project, where patients were on a significant scale able to access this new whole genome sequencing technology. So, many of the parents taking part in that project felt like pioneers, and there was really a lot of expectations around whole genome sequencing in delivering a diagnosis for those parents whoâd previously not been able to get hold of one.
Lisa: Yes, I strongly can resonate with a number of the points you made there, particularly the feelings of guilt. I must have asked myself a thousand times whether, you know, something I did do, something I didnât do, something I thought of, something I hadnât thought of [laughter], all those questions that swirl around, particularly in the small hours of the night when you feel particularly alone. And yes, I can completely relate to that. And also although SWAN UK is primarily for children and parent/carers whose children donât have a diagnosis, actually a number of the parent/carers on there will have children with diagnoses that are so very rare that absolutely, you know, very, very little is known. They might be the only parent â the diagnosis, for want of a better word, they may have received may just be a series of kind of numbers and genetic dot-dashes, forgive my laymanâs terms there, but it may not actually help them any further along in terms of feeling that they know anything further or the direction of, you know, where that will lead their children, and that can feel very, very isolating, Iâm sure, probably just as much for those of us who donât have that diagnosis.
Louise: Yeah, just to add to that, I think thatâs absolutely right, Lisa, and I just want to give a shoutout â at SWAN UK, we tend to support families who donât have a diagnosis at all, or, as you say, a small number of families who do but have been part of the SWAN UK family for so long that weâre very happy to keep them because of the support theyâre finding from other parents. We work really closely with another of our members, Unique, who are a charity that support parents in exactly the situation youâve talked about, where people have finally got a diagnosis and itâs that kind of relief of having a name, but itâs a super long name, and you find out youâre one of only three families in the world with that diagnosis. And so although thereâs a real I think comfort for people, perhaps if you have a five year old and youâre meeting a family who have a 13 year old and a family of a 19 year old, then you start to see a little bit about how your child might develop, but thereâs not enough kids affected that you can be really certain about that.
So, it gives you a little bit more information, but not the kind of wealth of information you were hoping for about how your childâs going to be impacted by a particular condition, and what the future might hold for you and for them. So, SWAN UK and Unique very much work alongside each other to kind of support families on whichever part of that journey theyâre on, because thereâs still a huge amount of uncertainty for families with those super rare conditions, as you say.
Lisa: Definitely, and Iâm sure youâll be familiar, Louise, yourself if you get time to go on the online communities and seeing the question that pops up quite regularly when somebody has received a diagnosis of, âCan we still remain part of the SWAN UK family?â And they very much use that word, family, because I think they do feel that, although all our children are different, there are children with physical, medical, cognitive, a combination of all the above syndromes, conditions, etc, they feel that kind of embrace of all being in a collective club of rare and unique and undiagnosed, and thatâs very comforting to the members.
Louise: Absolutely, yeah, I think that sense of belonging and being able to reach out to other families that youâve been on that journey with for many, many years. You know, many of our families join when their children are like one or two, and theyâre still with us when, you know, their children are 26, 27 [laughter], and that sense of having that community and that family and that belonging is really, really important to people, I agree. It makes a big difference psychologically to be part of a community you can reach out to and ask the questions that perhaps you canât ask to other people.
Lisa: Celine, can I ask you how many patients for the 100,000 Genome Project have had a no primary findings diagnosis back?
Celine: Well, back in 2021, there was a paper published in the New England Journal of Medicine, which reported that, in the initial pilot for the 100K, a diagnosis was found for around 25 percent of rare disease participants, and other studies looking at the diagnostic yield of whole genome sequencing have put the number anywhere between 25 percent to 55 percent, depending on the clinical indication. And we know that even already from the 100,000 Genomes Project, this pioneering project has led to more than 6,000 diagnoses being identified, and that number will obviously continue to go up as they explore the data and gather new insights. However, that still obviously leaves a significant number that wonât get a result from whole genome sequencing, as many as half of those rare disease patients, and that was really the basis of the study that Jana and I worked on.
So, we felt that there had been so much research really looking at the experience of parents who do receive a genetic diagnosis, and that a lot of attention rightfully does focus on the amazing successes of the 100,000 Genomes Project and genomic medicine more broadly, but actually that there is a considerable number of patients and parents and families who donât get a result, and we felt that it was important that we also focus on those parents and patients, and try and understand their experiences.
Lisa: Yes, you can feel, if your child, for example, is under multiple different care specialists, that it can be quite hard, when youâve just got this list of different names of things that are wrong, that you feel very much still out on the limb and forgotten about. But itâs clear that, from your work, youâre identifying that and pointing that back to the specialists, the consultants, to remind them that these parents and these children are still finding their ways through. Can I ask you, Jana, the study that was conducted, what would you say the main things from that study told us? Can you describe some of the emotions experienced by the parents, and what challenges that they have faced along that receiving the no primary findings diagnosis?
Jana: Yes. So, many participants really felt very strong disappointment and sadness on receiving that no result, and for many, it kind of reflected the feelings they had had when they first realised they had a child and there was no diagnosis for their condition. And as Celine said, this was such a new technology that people had invested a lot of hope in, and so many felt that it had been their last chance of finding a reason for their childâs condition, and that theyâd come to the end of the road with that no primary finding result. And, well, one person described it as another door shut. And people talked about the actual toll taken, the emotional and physical toll, and one person described feeling low for several weeks following the result. And some talked about the timing of the result. Somebody got it as a letter just before Christmas, and so their whole family holiday that theyâd prepared was marred by getting that news just before Christmas.
And it often seemed to leave parents feeling isolated and unable to contribute to normal parental roles, such as going to parent groups, etc, because they felt that other mothers particularly - as itâs mothers we were speaking to, other mothers, their experience of motherhood was so incredibly different to their own, and they felt a lack of support. And one parent actually talked about wanting to lock everyone in the house just to escape the feeling of judgement and pity from outside the front door. And some parents talked about finding it hard when other people would post on support groups that they had got results from the 100,000 Genomes Project, which was very difficult. And some talked about hope as finding it hard to keep hopeful but needing to keep hopeful. So, they talked of hanging onto a little bit of hope, as though that was quite an intense thing, which I think, Celine, youâll agree, that made us able to kind of identify that hope was really part of a coping mechanism for this whole process of going through this diagnostic odyssey.
Celine: Yeah, people sort of talked about not wanting to let go of hope and the importance of hope, and that without hope, there was no sense of wanting to continue this journey of trying to find a diagnosis, and that it was still very important to people. And I think that parents did understand that, even though a no primary findings result now, that doesnât necessarily mean that they wonât get a diagnosis at some point in the future. So, thereâs obviously the opportunity to do future reanalysis of the genome, particularly as we understand more about the function of different genes, and as new genes are added to many of the panels that weâre using in whole genome sequencing. So, I donât think not finding a result means that there is no hope in these circumstances, but for many parents, they did talk about hope being too painful, and not wanting to be let down again, and really preferred to focus on the here and the now rather than necessarily focus on the future.
Lisa: Yes, I can only speak from my own experience here, but I think I primed myself to actually forget about going on the 100,000 genomes sequencing because, having undergone genetic testing for certain conditions that they were quite convinced my daughter had from around the age of four months through to around the age of three years, Iâd gone to so many appointments and thought, âOh, thisâll be the time that I turn up and somebody will tell me this is what is the diagnosis.â And when I then joined the 100,000 Genomes Project in 2015 with my husband and my daughter, the genetic experience, the discussions that we had at the time were very helpful in that it was made quite clear to me that potentially we wouldnât get a finding, and actually that any information that did come forward was perhaps unlikely to be hugely beneficial to our family at that point. So, I was quite clear what potential finding would mean to us.
But I think in the back of my mind, subconsciously, I had hoped that, when we eventually got a diagnosis, it would â I donât know, bells, whistles, balloons going up, fireworks, etc. And then the experience of a letter thumping on the doormat, and I recognised the postmark quite quickly, and it was at that moment I suddenly thought, âOh gosh, I havenât buried all these feelings of hope.â Because I opened that letter with quite trembly hands, and then this diagnosis or lack of diagnosis, you know, nothing had been found, and it was a bit⊠I donât know if itâs been described as like a nail in the coffin experience, because I really hadnât realised I was still clinging to this hope all that time, and then again it was, you know, another, âNo, nothingâs there.â
And I think because of the work Iâve undertaken with SWAN UK as a volunteer, and being quite involved in wanting to sort of educate myself and learn more, I did understand that, even though we had no primary findings, it didnât mean that the study, everything was closed to us. It didnât mean, you know, that things wonât still be looked for. But equally, at the same time, it just meant that we had nothing yet to pin anything on at that point. And I think itâs quite hard to pick yourself up and dust yourself off again, to be like, âOkay, weâre still here, weâre still circling that drain,â as it were.
I think actually that takes us on quite nicely really, about what role hope has in the experiences of a child with rare and undiagnosed conditions. And again if I can just say that thereâs hope and thereâs realism, and somewhere along the way, if youâve been on the journey for quite a long period of time like ourselves, you have to try and find a way of living with that hope and realism all at the same time. So, weâre still hopeful that one day we might get some answers, but weâre realistic that day to day we need to focus on the difficulties or the experiences that my daughter has, so that we can manage to give her the skills to live her life to the very best of her abilities. Certainly, thatâs our experience. And also I think if Iâd let myself dwell forever on not having a diagnosis or a pathway specifically for that, it would have been quite difficult to carry on, pick ourselves up every day. What would you think about the role of hope there, Louise? What would you say your experience is from chatting to fellow parent/carers?
Louise: Yeah, I think youâve described it really eloquently and better than Iâll be able to do, but when we talk to people, the phrase I always have in my head is kind of hope for tomorrow and help for today are the two things that people are looking for. So, making sure that that hope for tomorrowâs still there both in terms of, you know, the NHS being really clear that it will provide support for individuals without a diagnosis, and there may be opportunities for reanalysis in the future as science makes future progress. And, you know, there is progress being made so fast at the moment in genomics and thatâs really welcome. So, making sure that people whoâve already had whole genome sequencing but not found anything continue to have access to that potential reanalysis I think is really important.
As youâve rightly said, Lisa, as well, thinking through in terms of hope for tomorrow, the opportunity to take part in clinical trials and to make that as easy as possible where treatments are being delivered, to have the opportunities to take part in trials for non-condition specific treatments, whether thatâs for epilepsy, which affects people across a whole range of conditions, or sleeplessness, which affects people across a whole range of genetic conditions. You know, there are both trials that only people who have a particular condition can take part in, and trials that are open more broadly, so making sure those opportunities are available as well, so that people have that kind of hope for the future.
But alongside that, I think itâs really important for the NHS to be clear with people about what help for today will continue to be available, and so we are working really hard with the NHS to emphasise the fact that when no diagnosis is possible, the NHS still needs to be clear to people about how they will be supported, whether thatâs through the genetics team or a particular discipline, perhaps the one that is the closest fit for their childâs biggest need, whatever that may be, that they can still access more joined up care. So, you know, who is the person in the NHS, if you donât have a diagnosis, whoâs going to help you secure referrals to speech and language therapy, to physiotherapy, to learning disability nurses, and to the package of care that your child may need.
Who is the clinician, if you donât have a clear diagnosis, whoâs going to be the person with the authority and the confidence to lead the multidisciplinary team, maybe up to 30 healthcare professionals who are going to support your child. You know, who is going to be the lead clinician thatâs going to pull that multidisciplinary team together and make sure that your childâs not being prescribed stuff thatâs contraindicated, or thatâs going to help one element of their condition but make another element worse. So, we are really trying to work with the NHS to make sure theyâre thinking through, where will that support be for the family in terms of their healthcare.
And alongside that, you know, many wider services like schools or social care or employers welcome the chance to talk to a geneticist or a genetic counsellor or nurse to understand what adjustments they might need to make for someone who clearly has a genetic condition but doesnât have a clear diagnosis. And so weâre trying to kind of make sure the NHS is both focused on the kind of science side and making sure that the hope for future findings is there, but also the help side, and making sure that the right package of care is still available for families who clearly have a genetic condition.
Lisa: Actually Louise, yeah, youâve really summed it up excellently there, and whilst I am hugely grateful to the NHS and the various services, I can say, hand on my heart, my daughter has a huge number of professionals involved, both from the health side of things and social care side of things, and actually the person that kind of holds all that together is myself. And because weâre under multiple different teams, every time a new medication, for example, is prescribed, I need to go back to our lead team, which in this case happens to be neuromuscular, and check that, for example, if gastroenterology have prescribed a medication, that itâs not contraindicated from a neuromuscular side of things and so forth.
Itâs all a bit like having sort of interlocking parts of a jigsaw, but perhaps no picture to follow [laughter], and that can be quite an isolating experience. And certainly, having chatted to fellow parent/carers, I know thatâs their experience as well. And I imagine, Celine and Jana, you found sort of similar experiences when conducting the research.
Celine: Yeah, so my PhD actually was focusing on the sort of journey for parents as they go through the diagnostic process, and one of the things that came out really strongly from that body of work was how the parents were really carving their own care pathway, how they had to sort of push and fight to access services, but at the same time were the gatekeepers for their childâs health. Having to make sure all the various teams and clinicians were kept up to date with all the different tests that they had and all the results. And, you know, at times, this could be really frustrating for a lot of parents, âcos they had to keep repeating their story over and over again, particularly âcos they didnât have a diagnosis. So, these parents really were having a very different parental experience to many of their friends and family, because their experience of being a parent to a child with an undiagnosed condition was really sort of as being a patient advocate, and as having to push and fight to access services.
Lisa: Yeah, itâs quite a unique experience. You are the specialist for your own child in that sense, I think would be the way Iâd describe it. And I suppose over the years, Iâve got so used to sort of trotting out different medical explanations in terms that you can almost sound like you know what youâre doing [laughter]. And a few times when Iâve been at medical appointments, and perhaps weâve met a new specialist or consultant, theyâve said, âOh, whatâs your field? Whatâs your area of expertise?â And actually you just think, âNo, Iâm just a specialist in my own childâ [laughter]. But thatâs quite an empowering feeling actually, so I guess that plays back into the feelings around hope and expectation, even with having an undiagnosed child.
Lisa: When I was recruited to the 100,000 Genome Programme, we didnât actually as a family receive genetic counselling specifically, and I know that this is something that is incredibly important to many families, and how that can support you sort of going forward. We were quite lucky in our experience in that we knew that our daughter was definitely going to be our last child, so we didnât have the thoughts and insecurities around potentially what it might mean for any future children that we had. But certainly as my daughter has got older and sheâs asking her own questions, and our older children are at a stage in life where theyâre looking at potentially having families in the future, I know that those things have come up, and weâre just still exploring what that will mean in the bigger picture. But can you tell us, Jana, really what can genetic counsellors do to help parents feel less isolated and better to cope with the uncertainty surrounding their childâs condition?
Jana: Yes, well, Iâm sorry to hear you didnât have any genetic counselling prior to going on the 100,000 Genomes Project, because that consent conversation right at the beginning, before the whole genome sequencing, is really important. Itâs important to know what the range of outcomes may be, so that it may be that you might get a result, you might get a variant of uncertain significance, or you might get no result. And parents in our study did suggest that their sense of isolation when they got a no primary finding result would have been alleviated if theyâd known how many were not getting results. So I think in the longer run, itâs 40 percent perhaps received a result, so thatâs 60 percent that didnât receive a result, so those parents were not alone, but they felt very alone. And some suggested if theyâd just had a leaflet really explaining that, and explaining that theyâd still contributed to research and that that had been, you know, a good outcome in a sense, then they would have felt better about it.
So, a lot of work can be done before the testing really, to explore how you might feel on that range of results, and then that way sort of prepare parents for how theyâre going to feel, and perhaps that helps them to have things in place, to know that it might be a vulnerable time with that letter, although that was particular for the 100,000 Genomes Project, to get the result in a letter in that way, and as you described, after such a long time, that youâd been able to forget that youâd been on the project. But to actually be a little bit prepared that it make take its toll on you might actually help with preparing oneself. It also might be helpful to include ways of promoting ways to enhance health and wellbeing for parents in terms of practical support, such as those things that youâre already attempting to access, like the respite services, school support, support groups, and thinking about psychological wellbeing and ways of managing stress, psychological support for parents, and possibly spirituality based resources as well.
And focusing maybe on what is known about the childâs condition even without a diagnosis, so whatâs likely to be beneficial, and support parents in actively coping, such as what research they might be able to access, and continued medical support. And also actually having a named person within the genetics service, so they have someone to go to for any follow-up that has a name, and so they donât feel isolated from the genetic service. And signposting to those external resources, such as SWAN UK, can be very important as well, of course.
Celine: I think itâs also really important to add that hope isnât necessarily lost when you donât get a diagnostic result. And in a sense, what can be really helpful is for genetic counsellors to reframe that hope, if you like. So, one thing that we talk about in our paper is that it might be useful for health professionals to ask a question such as, âIn light of the new information that we now have from the whole genome sequencing result, what are you hoping for now?â So in a way, itâs sort of reframing that hope, sort of giving it a different context.
Lisa: Definitely, and I think one of the things as well is that, because potentially for when parents were first recruited to a study such as the 100,000 Genome specifically in this case, that it might be quite a length of time between that initial recruitment and when the actual result comes out. And of course, in that time, with the advances in genetics, itâs sort of somewhat of a Pandoraâs box really, isnât it, in that weâre almost kind of finding the information out quicker than we actually know how to process it and what it potentially means. So actually if thereâs a genetic counsellor available to speak to those parents, or for those parents to be signposted to somebody who can say, âWell look, since you were recruited, actually this is happening, thatâs happening,â or, âThese research projects are happening,â personally, I can say that is going to be really helpful and handy, and would have been really useful. I just know that for myself anyway and my family, that if there was a leaflet or something that had given me a way of knowing how I could contact somebody in the future, that would be really helpful.
What ways do genetic counsellors use in maintaining a delicate balance between not creating false hope but also providing meaningful support to parents? What would you say around that, Jana?
Jana: I think as weâve already touched on, itâs that managing expectations from the outset when the test is offered. So, not generating too much hype or excitement, but setting those expectations, giving that information about the diagnostic yield. Also, informing parents that what people do experience has been described as a rollercoaster of emotions. Itâs normal. You might also want to explore people, not only what theyâre hoping for, but also the outcomes that they might be fearing, and giving them a chance to voice those, because they can be very powerful things as well. A diagnosis might not be what you want to hear, so there can be a lot of ambivalence around wanting a diagnosis when it might actually be a life limiting condition, that you didnât really want that certainty.
And also helping parents to explore how not receiving a result might feel, so that theyâve actually rehearsed it a little bit, and where they might go to when they need a bit of extra support. So, they already know, âI go and talk to my friends, thatâs where I get my support from,â so that theyâre kind of ready for it, and that might help them with that sense of isolation, but also validating these feelings. So, itâs okay, itâs okay to have that dip, itâs okay to feel, that itâs something that many people experience. And creating a safe space for people to feel that, so if they want to talk to a professional or a friend, that those feelings are validated.
And in that way, kind of with that pre-counselling really, helping parents to develop their own set of resources, so theyâve got those to draw on. And as youâve mentioned, Lisa, itâs like having your own resources also helps generate that feeling of empowerment and control. And as Celine has said, itâs really facilitating parents through that passage of reframing what youâre hoping for, reframing what the future looks like, if you had one picture of a future. You need to become comfortable with the future youâre now looking at.
Lisa: Thank you, Jana. Louise, if I can ask you really, weâve already touched on the role that SWAN UK can play for parents dealing with undiagnosed rare conditions, but perhaps if you could home in on that and explain in more detail the main focus of SWAN UK, and what that can do for parent/carers.
Louise: So, what SWAN UK primarily does is bring together parents who are in a similar situation. So, we have a team of amazing parent representatives, who Lisa is one, who help us shape the support that SWAN UK can provide, and really make sure that itâs based on a really strong understanding of what itâs like to be a parent of a child with an undiagnosed genetic condition, and an understanding of that kind of expertise that parents who have been on that journey themselves will bring. So, we have a series of Facebook groups. Some of them are for different regions, so people come into contact with other parents in their area who are going through similar circumstances. Some of them are more around age. So, you know, we have Facebook groups for parents who are waiting for a diagnosis or have got a new diagnosis, and then we have a group called SWAN Graduates, which is for children who are older and over 18, so their parents can come together and share their experiences.
So, itâs really to help parents be able to talk to one another, to share their experiences, to support one another, and often to ask for advice. Theyâre often kind of practical questions about, you know, âMy child needs this kind of wheelchair, has anybody been able to source that from somewhere?â âMy childâs having real difficulties eating at the moment, can anyone give some advice on this particular challenge?â âThis thing someone else has faced, how did you approach it? Where did you reach out for support?â So, that peer to peer advice and support is really at the heart of SWAN UK.
And then what we try and provide around that is access sometimes to information events, where thereâs particular issues that are affecting a lot of SWAN families. So, we hope over the coming year to have a series of information events targeted at families with children who donât have a diagnosis, and some of it is just trying to have social events and bring people together again. Weâve had, for example, an active dads group in Wales, whoâve been bowling and wanted to go axe throwing, and really they just want to come together with other dads who are in the same situation, and being able to talk to one another and provide emotional support to one another.
So, thatâs kind of the nub of SWAN UK and what we do, and then alongside that, that kind of fits in with Genetic Allianceâs wider goal, which is much more around campaigning for improved services. So for example, the Genetic Alliance UK team has worked really closely with commissioners in Wales, who actually commissioned the first SWAN clinic, which is in Cardiff. That was a two year pilot, to see what support could be provided both to help SWAN families get a diagnosis, but far beyond that, to make sure that the care for families who donât have a diagnosis is better joined up. And that we feel has been a real success. Again, there hasnât been a really high diagnostic yield, there have been very few new diagnoses, but the support provided to the families who are in contact with that clinic, in terms of helping them access better joined up care both from the NHS and from services more widely, has been brilliant. And weâre currently working with NHS England in the UK, who are exploring an opportunity to commission two SWAN clinics in England.
So, that trying to kind of improve services, and then the third aspect of that is just working generally with the new genomic medicine service alliances as they emerge across England, to try and make sure they are thinking through what support they will need to continue providing to families whoâve gone for whole genome sequencing in future, not through a research project like 100,000 Genomes, but just through routine clinical practice and routine clinical diagnostics, what support will they need to provide for families who go through that process and donât get an answer. And that wonât change the support they will need from the NHS. It will just mean that perhaps that clinic needs to play a more active role in helping them access those services. So, all of that kind of campaigning to have better services for family who have an undiagnosed genetic condition continues as well.
Lisa: So, I think one of the things really just to finish off today, is of course looking at the future. Considering advancements in technology, would you say that future reanalysis of the 100,000 Genome Project is going to yield additional insights? Celine, can I ask you to comment on that?
Celine: Yes, absolutely. As we understand more about the role and function of different genes, and as new genes are added to the panels, we will definitely be able to provide a diagnosis for more parents and more families. But I think we donât yet necessarily know exactly what that reanalysis will look like, and itâs not really clear yet how this will work in practice.
Lisa: And Louise, would you have anything else to add to that at all really?
Louise: No, I think it is just that hope for the future and kind of help for today. I think the NHS needs to be equally clear about, you know, thereâs some amazing investment by the UK government in genomic research, and thatâs brilliant and we want that to continue, but equally we want the investment to be taking place into routine clinical services and diagnostic services, so that we can talk to people both about the hope of potentially getting a diagnosis in future, but making sure that the help continues to be available for as long as they donât have a diagnosis, and that help for families who donât have a diagnosis is going to be just as important. And what we try to ask for is both real clarity around what the NHS can provide, and really clear signposting to organisations like SWAN for families that continue to not have a diagnosis. And again, just to give an equal shout out to Unique, who are able to support families who have an ultrarare diagnosis, where perhaps theyâre the only person in the country with that particular diagnosis, or one of a handful of families around the world. Signposting to that peer to peer support will continue to be a really important part of the process as well, so that families can help one another, learn from one another, and just give each other support that they are kind of sharing that same journey and walking alongside one another on that journey as it continues.
Lisa: And bringing this podcast to a close, can I just ask you really, any final thoughts, anything that you would sum up from your experience of researching the no primary findings and where we now are today?
Celine: I think the main thing for me is just to sort of make it clear to parents that a diagnosis isnât necessarily a magic wand, even though it is obviously very important to a lot of parents. But that even without a diagnosis, we still have the opportunity to manage patientsâ symptoms, and often a diagnosis doesnât make a substantial difference, because parents are sometimes left with a lot of uncertainties and a lot of unanswered questions. So I think, and as Louise and Jana have said before, itâs really sort of on focusing what we do know, and thinking about what we can offer and what support we can provide to parents and families even without a diagnosis.
Lisa: Thank you very much to our guests today, Jana Gurasashvili, Celine Lewis and Louise Fish, for joining me as we discussed the impact of a no primary findings result. If youâd like to hear more like this then please subscribe to the G Word on your favourite podcast app. Thank you for listening. Iâve been your host, Lisa Beaton. This podcast was edited by Mark Kendrick at Ventoux Digital, and produced by Naimah Callachand.
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In this explainer episode, weâve asked Helen Brittain, Clinical Lead for Rare Disease Diagnostics at Genomics England, to explain what a variant of uncertain significance is, in less than 10 minutes.
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 youâve got any questions, or have any other topics youâd like us to explain, feel free to contact us on [email protected].
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/What-is-a-variant-of-uncertain-significance.docx
Naimah: What is a variant of uncertain significance? Today Iâm joined by Helen Brittain, whoâs the clinical lead for rare disease diagnostics at Genomics England, to find out more. So first of all, Helen, before we dive into the topic, Iâd like to go one step further back and ask you to explain what is a gene?
Helen: A gene is effectively a section of our DNA, which is our genetic code, and it contains an instruction, something important about how we grow, how we develop, how we function as a human. Humans in total have around 20,000 genes, which is our complete set of instructions, to tell us everything we need to know about ourselves.
Naimah: So, what are gene variants then, and do they all have an effect?
Helen: Variants are effectively differences within genes. So genes, like I said, are instructions, and they have a particular way that theyâre spelled out and structured, so that the body can understand them and make sense of that instruction. A variant is where thereâs something different about the way that that gene is spelled out or structured that could affect how it works, and basically a variant is a difference to what we expect to see.
Naimah: And do all of these have an effect?
Helen: So no, not all of them will have an effect. Some differences or variants within a gene may not affect the way it works at all, whereas others might alter that gene so significantly that it canât do its job anymore, and could be very significant for that personâs health.
Naimah: And how do we find these gene variants?
Helen: Gene variants are exactly what weâre looking for when weâre trying to find a diagnosis for somebody. So, somebody with a rare condition is likely to have an underlying difference within their genes that would be the explanation for it. Weâre finding these through doing genetic testing or genomic testing, so looking at an individual gene, a series of genes, or even across someoneâs entire genetic code, through whole genome sequencing, and we find these variants through doing that testing.
Naimah: And this might be a good opportunity to mention our other Genomics 101 episode on genetic testing, if youâd like to find out some more information on that as well. So, moving on with the next question, how is a variantâs significance determined?
Helen: Variants, as we say, come from the genetic tests we undertake, and there are a team of people who look at and try to determine what effect that variant might have on that person. This is the majority of the time the work done within the laboratory teams, through the clinical scientists, who have expertise in understanding the impact of variants within a gene, and they work together with other clinical representatives, like the clinician looking after the patient, to understand that patientâs disease in as much detail as they can, to try to pull all of the information together and determine whether that variant is making a difference or not.
They would look at a lot of different pieces of information to try to work out, could this be the reason behind that personâs genetic disorder? And that might be things like have we seen it before, can we predict the effect of that variant on the gene? And we have to understand how variants within that gene cause a condition to be able to match up against the variant thatâs seen, as to whether that would make sense for that individual. So, itâs a lengthy process but an important one, to make sure that weâve got the most accurate information about that variant, and the understanding about that in that personâs health and development.
Naimah: So then, what would be a variant of uncertain significance?
Helen: So, the output of that clinical scientistâs work looking at whether a variant is significant or not comes out into five categories, but three main groupings. What weâre looking for obviously through doing genetic testing is to try to find a diagnosis for somebody, and a diagnosis would be a place where we are confident that that variant impacts on that gene and leads to the condition that that person is presenting with. So, that would be a diagnosis on one end of the spectrum of what we might find.
On the very other end of the spectrum are variants that donât make an effect on the gene, that would be benign. We would call those harmless variants, things that donât change the gene and wouldnât be expected to be associated with a condition.
And then, in life thereâs always a grey area, and the part in the middle, between being confident about a diagnosis on one end or being confident that that variant really doesnât impact the gene and is harmless. We have variants that we find that we do not yet understand, and thatâs basically because our knowledge as of when the variant is looked at is good, but itâs not perfect. There could be more to learn about particular variants or particular conditions, but at the moment we just donât have enough information to be sure one way or the other. And thatâs really important, weâve got to get it right, so we do have this grey area in the middle, which are the variants, differences in the gene, where the significance of them on that person is uncertain.
Naimah: How often do we find these variants of uncertain significance when weâre trying to genetically diagnose patients?
Helen: They are relatively common for us to encounter, and thatâs for a number of reasons, I would say. I think that we know a lot about our genes, and our knowledge has come on leaps and bounds, and itâs still improving at a rapid rate, but we donât know everything yet, so there will be areas where we havenât met a particular variant before, or we canât predict how it might affect that gene, or thereâs some uncertainty about it because we donât have full knowledge yet. So, it does happen relatively commonly, and it probably happens more commonly the more genes or the more information weâre looking at. So a test looking across someoneâs genome, like whole genome sequencing, weâre more likely to come across these things than if weâre doing a very targeted test looking at one specific gene that we understand very well, for example.
Naimah: And how can knowing the significance of a gene variant be impactful for clinicians and the patient?
Helen: This is really important, knowing the significance of a variant is key. Itâs fundamental to genetic testing, because we are trying to make a confident diagnosis for somebody, and we have to get that right, because if we make a diagnosis in somebody there are lots of knock-on implications of how that information is used to inform the healthcare of the individual who has the condition, or maybe even to inform their family members, who could be at risk of the same condition. Obviously, we share our genetic information amongst our families, and so a genetic test might be used for a family member as a result of a diagnosis in one individual within their family.
And of course, in some situations, that might lead them into either needing screening for a particular condition that could happen, or being removed from screening if they donât have the genetic cause within their family. Equally, people might make choices surrounding whether to extend a family or reproductive choices around the knowledge of a genetic condition within a family. So you can see, the implications are huge. Itâs really important this is correct.
Naimah: And finally, I just wanted to ask, can we reclassify variants of uncertain significance?
Helen: Yes, thereâs real need to do this because people are wanting genetic diagnosis answers for understanding, and for all of the implications we just mentioned about why are diagnoses important. So yes, we can reclassify variants of uncertain significance, and that can happen in different ways. Itâs not always possible straight away, unfortunately. So, what we often need is time, and that is time to understand that variant a bit better, and that might be through seeing it again in other people, maybe who have the same pattern of health problems or same picture in terms of their rare disease, and we start to understand, okay, that might actually add up to suggest that that variant is affecting the way that gene is working. Or equally, we might see it in other people who donât have the same rare disorder, so weâre starting to see, well actually, maybe itâs harmless and itâs just part of the natural genetic differences we all have.
The other way that we can understand variants of uncertain significance better would be through research, so for example researchers looking at designing studies to try to see if they can make a model, for example, with an animal who might have the same type of variant, and see if that causes an effect on their health, so learning specifically about that variant through research could also help. And there are things that clinicians also actively try to do, and this is why we work together with the clinical scientists is to understand, are there other people within the family with the same rare condition, and would it help to test them to see if they also share the same rare variant. And sometimes that can help, not always. So yes, we really want to try to reclassify variants of uncertain significance, and as far as possible, we will, but sometimes they do just need that time for us to build that bigger picture.
Naimah: That was Helen Brittain explaining variants of uncertain significant. Iâve been your host, Naimah Callachand, and if youâd like to hear more explainer podcasts like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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29 February marks Rare Disease Day. This day is an opportunity for the rare community to come together to raise awareness of the common issues affecting those living with rare conditions. A rare condition is a condition that affects less than one in 2,000 in the population, and although rare conditions are individually rare they are collectively common. It is estimated that there are over 7,000 rare conditions. Around 80% of rare conditions have an identified genetic origin.
In this episode of the G Word, our host Julia Vitarello, Founder and CEO of Milaâs Miracle Foundation, is joined by Rich Scott, Interim CEO for Genomics England, and Ana Lisa Tavares, Clinical Lead for Rare Disease Research at Genomics England, as they discuss challenges for those living with a rare condition and the work being carried out across the genomics ecosystem to support them.
Julia is the mother of Mila, a young girl who was diagnosed with a rare genetic condition called Batten Disease, and in this episode Julia takes us through Mila's story, and how she hopes to help many more families access treatments for their children.
"So when parents, children, are diagnosed whether itâs a fatal or life-longing debilitating or difficult disease, if you know that whatâs being learned from your child both from just the genomics to the potential treatments thatâs helping the next child, that helps parents like me be able to continue living."
You can find out more about Mila's story in our previous podcast episode with Rich Scott, Julia Vitarello and Dr Tim Yu.
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/Rare-Disease-Day.docx
Julia: Welcome to the G Word
So my life at that point seemed to just disappear in that moment, all the things that had mattered to me were gone; I knew there was something wrong with my daughter but I had absolutely no idea that a typical child who was outgoing and active and verbal and had friends could suddenly lose all of her abilities and die.
My name is Julia Vitarello, and Iâm your host for todayâs episode. Today joining me in conversation is Rich Scott, Interim CEO for Genomics England, and Ana Lisa Tavares, Clinical Lead for Rare Disease Research, also at Genomics England. Today weâll be discussing challenges for those living with a rare condition and the work being carried out across the genomics ecosystem to support them. If you enjoy todayâs episode, please like, share and rate the G Word on wherever you listen to your podcasts.
The 29th of February marks rare disease day. This day is an opportunity for the rare community to come together to raise awareness of the common issues affecting those living with rare conditions. A rare condition is a condition that affects less than one in 2,000 in the population, and although rare conditions are individually rare they are collectively common. It is estimated that there are over 7,000 rare conditions. Around 80% of rare conditions have an identified genetic origin.
Before I get into speaking with Rich and Ana Lisa, I wanted to share my story and my daughter, Milaâs, story. My life as a mother started really like anyone elseâs, my daughter was perfectly healthy, her name is Mila. For the first three or four years of her life she was like any other kid. I live in Colorado in the United States, my daughter was a skier, she was a hiker, she was rock climbing, she was incredibly active and singing songs and swimming and riding bikes. But around four yearsâ old she started tripping and falling, she started pulling books and toys up closely to her face; she started being covered in bruises, getting stuck on words and repeating her sentences and I brought her to about 100 different doctors and therapists around the United States to try to figure out what was going on with her.
Around four yearsâ old I started speaking with orthopaedic surgeons, with ophthalmologists, with neurologists, with speech therapists and each one of them, you know, told me pretty much that I was a crazy mom and that my daughter was typical and normal and that she would grow out of these sort of strange symptoms that she was having.
By the time that she was six yearsâ old, I had had enough and I was crying on a regular basis, no doctor could help me and I was tired of lugging my daughter, who was now covered in bruises and tripping and falling and stuttering, together with my newborn son at the time, kind of around the country only to be told that I was crazy. And at that point at six yearsâ old I brought her into the emergency room in the Childrenâs Hospital Colorado, near where I live. She was in there for about a week and underwent a battery of tests and at the end of that week I was told that my daughter had a rare genetic condition called Batten Disease and that she would lose all of her abilities and die in the next few years. So my life at that point, first four years of my life seemed to just disappear in that moment, all the things that had mattered to me were gone. I knew there was something wrong with my daughter but I had absolutely no idea that a typical child who was outgoing and active and verbal and had friends could suddenly lose all of her abilities and die.
After crying on my closet floor pretty much most of the day for a few weeks I picked myself up. I started to read white papers, I started to go online and learn about other rare conditions. I started to speak with parents that had fought for their children with physicians, with researchers, and did everything I could to kind of figure out if there was even a glimmer of hope. And what I was told at the time at the end of 2016 was that there is almost nothing that could be done and very little was known about my daughterâs form of Batten Disease. But that there was a tiny glimmer of hope that we could maybe stop genetic disease, and thatâs all I needed. I started Milaâs Miracle Foundation, which is a non-profit organization. I started telling Milaâs story and taking care of my kids by day and trying to fight and learn and raise money by night and I started a gene replacement therapy because it was the only option that I could take on as we didnât know much at all about the disease, and by replacing it, it was kind of the only thing that I could do, but it was going to take many years and millions and millions of dollars and I knew that it wouldnât be in time for my daughter.
Along the way, there was something a little bit unusual which was that my daughter had an auto recessive disease which meant that she needed to have a mutation in the same Batten causing gene from her mom, myself, and her father, and they could only find one of these two. That led me to learn about whole genome sequencing, which was kind of the most extensive way of looking at Milaâs genome to figure out where this missing mutation was. And in that search I crossed paths with a Dr Timothy Yu at Boston Childrenâs Hospital, and he volunteered with his lab to help me find this missing mutation that no other lab could possibly find. And within a few months and a lot of work, a lot of late nights and weekends and staring at screens, through whole genome sequencing, the team was able to find Milaâs missing mutation and finally diagnose her fully with this rare form of an already rare Batten disease.
That is where Milaâs story changed and turned direction. At that point, a recently approved drug for spinal muscular atrophy was on all neurologistsâ minds at that moment because it had just been approved in the US by the FDA and in other countries, and it was a game changer, these children were dying and on respirators and in wheelchairs you know at the age of two and with this new drug they were actually living, many of them were living long lives and were active and happy and healthy and going to school. And Mila looking her whole genome sequence was able to kind of fit that same criteria, and so the doctors, including Dr Yu said, âWhat if we did the same thing for these children? What if we made a drug like this for Mila?â This drug called Antisense Oligonucleotides, or ASO seemed to be a good fit for Milaâs mutation. And so a drug was made for Mila and named after her called Milasen and it was a race against time for an entire a year with a team of honestly hundreds of people across academics and industry, I was fighting to try to raise the money and awareness and working with a scientific team. And one year after Mila was diagnosed when she turned seven yearsâ old, we moved to Boston and Mila began receiving Milasen, which was named after her, and only in that moment in time did I realise not only what a big deal this was for me as her mother, but what a big deal this was for science.
She was the first person in the world to receive a medicine that was tailored just to one person and it was named after her because there was no-one else in the world they could find that shared that same mutation.
When Mila began this, you know, I didnât know what to expect but I knew that she was going to lose all her abilities and die if she didnât receive this. And so once she started receiving this within just a few months, her 30 seizures a day went down to nothing; she had occasional small tiny seizures that were barely visible but her quality of life was incredibly you know improved, not to mention our familyâs because she was no longer thrashing and smashing her arms and legs up against walls and tables.
She had been slumped and could no longer sit up. She could no longer hold her body up and take steps with my support from behind and after Milasen she started being able to do that even walk up the stairs with alternating feet with me supporting her from behind. She also had received a G-tube and was receiving all of her nutrition through the G-tube and after Milasen she started eating by mouth, it wasnât perfect, but she was eating pureed foods, and being able to swallow better and probably most importantly she was able to smile and laugh at the funny parts in the books and the stories that I had been reading and singing to her and that she had kind of really not been responding to as much before Milasen and some of that came back.
So, a year into this everyone was quite shocked that Mila had done so incredibly well in this first year despite how progressed she was, progressed her condition was. Unfortunately in the second year it was during COVID and it was unclear whether or not Milaâs disease had kind of stopped or whether it was slowly progressing and in the third year Mila started having problems associated with her rare condition and I was faced as a mother with the most horrible decisions anyone should ever, never, never, never have to face to decide what Mila would want if she were able to talk and tell me whether or not this was a life that she felt like she would want to live. And after three years on Milasen, which was three years ago almost this week, Mila died and in many ways my life as I knew it was kind of over. Iâm a very positive happy person and I have a son and I continue getting up every day and pushing through the day but Iâm not sure how any parent makes it through days, weeks, months and their whole life without their child physically there with them.
Ana Lisa: We can really hear the perseverance that you had to get a diagnosis through whole genome sequencing eventually for Mila. Can you tell us a little bit more about that process and what that diagnosis, what did it mean for Mila and for your family?
Julia: When Mila was first diagnosed with Batten Disease, one of the missing mutations could not be found by any lab. I did research and found out that whole genome sequencing which at the time was very, very hard to find a lab that would do it or anyone that would do it in the United States, I did learn that that was really what was needed in order to try to really get down to find the underlying genetic cause of Milaâs disease and give her a full diagnosis. So once we managed to have Dr Yuâs lab at Boston Children's Hospital carry out the whole genome sequence, obviously we were able to then find exactly where the broken, underlying broken kind of genetic mutation was and why that was important was for two reasons: 1) was so that we could actually have a diagnosis and even though it was the worst diagnosis we could have ever asked for, at least there was an answer and for so many years I didnât have an answer and there is nothing worse than seeing your child, you know, having all of these different symptoms and problems and having you know tens, if not hundreds, of different doctors and therapists tell you that they donât know and maybe youâre just a little bit over-worked and over-worried about things, and having no answer and no idea whatâs wrong is like living in this limbo thatâs just terrible.
And so whole genome sequencing allowed for us to have a full diagnosis for Mila, and it also allowed us to use that data since it was truly the precise place where, you know, we could find the precise plan where her gene was broken. It allowed the researchers to then also think about what could be done about it as well, which is the second thing a parent thinks about after they have the kind of relief in some ways, which is a strange word to use but itâs true, of knowing what is wrong and then thinking, âWhat could I do about it now?â And so for me I would say thatâs how, Ana Lisa, thatâs how I reacted to that, is there was enormous relief initially, which is just the weirdest word ever to use for that but at least I felt like I wasnât crazy and that there was an actual reason and that it allowed us, allowed me and others to think what kind of action can we take now.
Rich: One of the things that often strikes me, Iâm a clinical geneticist by background, just like Ana Lisa, is how often particularly several years ago when we were in a different situation, it depended on families and parents pushing and pushing and pushing and asking, thatâs something I think in the UK weâre really lucky that there have been changes in terms of availability of testing. Julia, as you know, we were set up ten years ago initially to run a project, a research project in partnership with the NHS called âThe 100,000 Genome Projectâ asking the question about whether whole genome sequencing could be used in a diagnostic setting. Whole genome sequencing had just emerged as a thing that could even be conceived of as affordable in a healthcare system back then, and we worked with the NHS and tens of thousands of families with rare conditions and people with cancer to ask that question and again, weâre really proud of what that work and our partnership with the NHS has led to, which is now in the UK.
There is the availability nationally of whole genome sequencing to test in certain settings including in rare conditions that are hard to solve in this sort of way and itâs one of the things which has really changed the way we can go about this, but we also know that thereâs still, itâs still hard often to identify who should be seen by a specialist who might do a test and so on. But it has really changed things and I think itâs hearing from families like yours about how challenging it is and thinking about how we turn, looking across all of the story that you told us of everything you went through, how we can make that be something where we can make it be more systematically available and work for many more people, and I know your phrase from Mila to millions really strikes a chord with me, and I know with the NHS mind-set here in the UK where itâs about equity of access and I think that mind-set that you bring is so important.
Julia: Yes, Rich, I think itâs a really good point you know, because a lot of parents like myself, weâre talking about probably millions around the world and tens of thousands just in the UK alone, spend so much time going from one physician to another and to a therapist and it takes an enormous amount of energy and time in a family thatâs already dealing with pain and confusion and not understanding whatâs going on, not to mention usually that child, in my case, Mila, is having problems that itâs not easy to leave the house and get in the car and go to all these appointments. And the more we can push towards whole genome sequencing as one of the first places to go, if not the first place to go, the more itâs going to cut that sort of diagnostic odyssey down to the very bare minimal.
And so of course a dream would be is that any child that has, I like to think of it as soon as you kind of have more than one symptom that shouldnât normally go together, that sort of has a little red flag that goes off and in most parts of the world right now no physician wants to scare a parent like me, itâs happened a number of times to me where a physician has said, âWell, you know, there is this rare condition but Iâm not going to bring that up because itâs so rare that the likelihood that your daughter has that, I wouldnât want to scare you.â But the more we can move towards whole genome sequencing right away to help with that answer that could cut months and very often years from that odyssey, and that is where we need to be, we canât have the tapping on the knee and stacking up blocks and running down the hall for months and years just to figure out whatâs going on.
Ana Lisa: And I think Rich also there said a power of having a national healthcare service where patients who are having whole genome sequencing can also decide whether they wish to consent to be part of research and combining that with a national genomic research library and then the ability to work so closely with the NHS and go back to patients if there is a new diagnosis that could benefit them is really powerful I think, and thatâs definitely one thing that weâve also learnt from these big whole genome sequencing efforts is that our knowledge is continuing to develop and some people will get a diagnosis from that immediately and weâve got amazing colleagues working on diagnostic discovery looking at whole cohorts of patients now who are having whole genome sequencing and thatâs also been really informative and allowed a lot of new diagnoses identified also through research and through these efforts to be found.
Julia: Absolutely and I think that the UK is incredibly well suited to have such widespread sort of country-wide whole genome sequencing project like what Genomics England has done because you have one system where all of the clinical and genetic data can all come in and kind of be analysed both for like you said diagnostics but also it could be, if families and patients are interested, right, in contributing to the research which then comes full circle and helps the entire system benefit from better treatments you know and better understanding of diseases.
Rich: And that point of sort of thinking about how to move things forward, so the NHS has a service based in Exeter which is addressing the question where children are on intensive care, where often intervention is needed really rapidly to make a difference, so thatâs one of the examples where sort of thinking about making sure that service is available early and rapidly is being set up and thatâs been really successful and identifying a cause where that really changes the care of that child on intensive care.
The other area where weâre working really closely with the NHS at the moment, as you know, Julia, and in fact I think this was probably one of the reasons we first came to talk to you was thinking about our newborn genomes programme where if you like, the big question there is saying we know that there are a few hundred conditions that are within that longer list of rare conditions where there is a treatment available routinely if the diagnosis is made, and saying could we use whole genome sequencing alongside existing newborn heel prick testing which in the UK currently looks for nine, shortly to be ten, conditions. So weâre just about to launch that programme and that will sequence the genomes of 100,000 babies born at maternity hospitals, not selected for children where thereâs something, a concern, raised, but any baby at that hospital would be eligible for the family to choose to join that research programme and really to ask that question about whether this is something that we should offer to all babies developing the scientific evidence around it, learning about how you might implement it in practice, and also having conversations about how one might do that, what public attitudes are to it and so forth, developing evidence that can move us forward in that area too.
And back to Ana Lisaâs point about improving knowledge, we know that today there are a certain number of conditions that one might think are comparable to those nine that are currently looked for in the UK on the heel prick that we could use genetics as a way in. We also know that through the sort of innovation and the new knowledge that you mentioned that was relevant to Mila, that list might grow quite considerably in the coming years, so itâs thinking about how we set ourselves up to make sure that weâre able to take advantage of that to its full.
Julia: Yeah, and I think itâs a great, Iâm glad you brought this up Rich because the UK really is leading the world in this, there is no-one else that is doing whole genome sequencing at birth, and ultimately, thatâs where we need to be. You know itâs not going to happen overnight and like you said, the purpose of this is really to learn a lot about how and if to roll this out maybe in a larger scale way across the UK. But ultimately, you know, as Milaâs mom, I think all the time about you know how incredible what I saw at a very progressed state for Mila with this treatment and the only way to actually really truly help Mila and other Milas is to get to these children early enough so that theyâre diagnosed before they have symptoms and theyâre treated before they have symptoms. And the way to move towards that is to at least have efforts like the project, you know, the newborn screening project so that we can get to children, find them before they have symptoms, treat them before that and from what I saw from Mila I feel pretty strongly that if Mila had received Milasen at birth she might never know the effects of Batten Disease, and we as a family might never know what itâs like living with a rare condition, and this is a step in that direction to help.
Effie Parks: Hi there, Iâm Effie Parks, mom to Ford, who lives with a rare neurodevelopmental disorder called CTNNB1 and the host of the Once Upon a Gene podcast. Our show connects families facing rare diseases, offering stories from parents, insights from experts and discussions on everything from navigating grief to exploring genetic advances. Itâs a space for understanding, connection and empowerment. For support and inspiration on your rare disease journey, subscribe to the Once Upon a Gene podcast on your favourite podcast app and letâs navigate this path together.
Ana Lisa: Julia, Iâm interested to hear what you think the development of individualised medicines like the N1 treatment Mila had what that means for the sort of collaboration thatâs required across the genomics ecosystem to achieve that.
Julia: Yeah, thatâs a really good question. Itâs been seven years that Iâve been thinking about this kind of individualised medicine concept, you know, as Mila kind of became the pioneer in this field and Iâm not a scientist, Iâm not a physician, but Iâve learned a lot because Iâve been fortunate enough to be part of thousands and thousands of conversations, including with all of you and others, Genomics England, and around the world and I think what I learned and what Iâve learned so far is that when you have a genetic condition most genetic conditions are individually rare and unfortunately that doesnât make them very suited to have anyone go after a treatment for them because really the only way to connect a patient, a child like Mila, to a science or technology is if theyâre lucky enough, and I hate to use the word âluckyâ but theyâre lucky enough to be part of a large kind of cohort of people, and that allows them to be, you know, commercially viable, so a company will be maybe develop if theyâre lucky, a treatment for that, for those people.
The only other option is this sort of like Herculean effort of which myself and Dr Yu and others went through, we had to raise millions of dollars and get hundreds of people to get on board and develop a novel medicine for one person â now how scalable is that? How many times can we do that, right? And so the only people that really have access to medicines today with genetic conditions are those that are fortunate to be part of one of these two groups, but what about everyone else which is 95% of the people?
And so I think what the field is learning is that we kind of have the patients and weâre finding them, especially thanks to Genomics England and others, weâre starting to find them more rapidly earlier, more of them, and we have these technologies to be able to not only find them but to also treat them but we just do not have the infrastructure and the processes to connect them, we have clinical trials and we have these sort of named patient route but we donât have anything else. And so I think the genomics community, especially in the UK because itâs so well suited with all the efforts that weâve just brought up, is really well suited to kind of try to work together to allow for access kind of no matter how many people could benefit, itâs not only one, it could be six or 20, or 200 or 500. Right now there is no access for them. So I think that the UK is really well suited, starting with whole genome sequencing, thatâs where it begins, it begins by identifying patients early enough and getting the data thatâs needed in order to diagnose them and also to help with the treatment you know, and so this is how I think the UK is really leading the world right now, including in the recent announcement of the rare therapies launch pad, which Genomics England is part of, I am part of, others are part of, Oxford Harrington Rare Disease Centre, the MHRA, others are all part of really trying to be dedicated to building the infrastructure and resources and processes that are needed to connect the patients to these technologies that exist today.
Rich: Iâve been really inspired by the conversations and the drive that you, Julia, personally have given to those conversations. And I think whatâs really interesting and I think itâs relevant more broadly than just in rare therapies particularly, but I think that challenge of recognising the need for the system to change to be able to respond to evidence and make the response proportionate to the expectations of various people, the patients or the families who are receiving it, the system as a whole, these sorts of therapies and rare conditions as well, are just not the shape that works well with existing paradigms, but I think itâs relevant you know, in other settings as well.
Iâm really interested in some of the conversations that Iâve had with you before about balancing risk and understanding how to get that right and the fact that that really needs an open discussion in public to also understand the journey and the situation that families find themselves in. I wonder if you could tell us a bit about your perspective on getting that risk balance right?
Julia: Thanks for bringing that up, Rich. I think itâs really, really important because to me the way we think of risk and benefit and the risk tolerance maybe is a better way to put it is the foundation of the house that weâre building. So, you know, the regulatory process and everything behind that are built on top of how we think about risk. And one of the things that I regularly think about is children that have end stage cancer, and that we as a society have accepted an enormous amount of risk for a child at end-stage cancer that has no other options thatâs going to die no matter what, probably very rapidly and that if they donât respond to kind of some of the main line treatments then to turn to an experimental cancer treatment which carries a very high risk is considered very acceptable by our society and that everyone, the clinicians, the families, the regulators, everyone is willing to take that risk for that child because theyâre going to die otherwise. And theyâre willing to spend money and theyâre willing to take the risk and often perhaps to buy that child maybe three or six months of life.
So then if you look at Mila and if I tell you that instead of having a rare condition that she has an end-stage genetic disease, and I use the words from cancer, from oncology, is now suddenly the discussion changes a little bit, so Milaâs going to die no matter what, no child has ever lived with her form of Batten Disease and sheâs going to lose all of her ability, so we know the risk of not treating Mila. The risk of treating Mila in this case was an antisense oligonucleotide, which is a modality thatâs been around for 30+ years, tested in animals and more frequently in numerous humans across different sort of trials. And the labs that worked on Milaâs medicine felt that it was safe enough and hopefully efficacious enough. And at that point why is the hurdle so exponentially higher than what it would be for a child with end-stage cancer? The way that we are thinking about these children with end-stage genetic disease and end-stage cancer, is drastically different, so we need to first, to your point Rich, we need to start realising weâve already set that precedent, we donât need to be having this discussion again. We know the risk weâre willing to take for a dying child when thereâs no other therapeutic, no other option and theyâre going to die no matter what. So the risk of treating Mila, versus the risk of not treating Mila is black and white and we need to do our best and then we need to not only treat Mila but we need to learn from the treatment of Mila. We need to collect those learnings, they must be iterative learnings so that the next child thatâs treated with an individualised different ASO or different medicine that they donât happen in silos, but that all of this knowledge comes together so that the second and the third and the fourth and the tenth and the twentieth, the process gets better and faster and eventually cheaper so that itâs accessible.
Rich: Yes, and thatâs very much back to Ana Lisaâs point on the link and for diagnostics too on continuing to learn and creating a system that recognises that thatâs crucial to offering the best care today but also in the future and being able to make proactive decisions more confidently if youâre a policymaker, knowing that youâll continue to learn, you donât have to pretend you know everything today.
Julia: Itâs very meaningful for parents. So when parents, children, are diagnosed whether itâs a fatal or life-longing debilitating or difficult disease, if you know that whatâs being learned from your child both from just the genomics to the potential treatments that thatâs helping the next child, that helps parents like me be able to continue living. And so you know, research is this kind of generic word, I wish there were a better word for it. Really what it is, is itâs learnings and itâs what can be learned from my child that can help the next child?
Ana Lisa: And then that learning requires a lot of collaboration, which is the super important part I think of your story.
Julia: Yes, it does, it requires a lot of people starting with those diagnosing the children with whole genome sequencing all the way through just to the clinicians who are in the NHS, not to mention the researchers who are then looking at the data and bettering their understanding.
Ana Lisa: I think there are also, maybe one can extend some of those parallels as well, in that I think currently we sometimes think of an individualised therapy of NF1 as being something that takes a lot of time and benefits an individual, and actually if we can really collaborate we can really set up processes that work across the ecosystem and keep learning, then Iâd love to dream that actually this could help many, many different patients, with many, many different types of rare conditions because actually weâve learnt how to target a little bit more at source, perhaps a particular type of genetic variant, and so a bit like cancer, weâre not thinking about breast cancer, weâre thinking about what sub-type, what genetic causes there are and targeting those, and if we can apply that one day more broadly across rare conditions then it might be that actually once youâve learnt a certain amount, that you could scale up and treat many, many different conditions, not dependent on their frequency in the population.
Julia: Yeah, thatâs a great dream, I share that dream. Rich, what is your, youâve been in this for many years, whatâs your dream for the next five, ten years?
Rich: I guess I have, I think thereâs two aspects to it. I think thereâs two, I think thereâs a lot of distance left to run for us improving on the diagnostics and I think thinking back to your conceptualisation of it Julia, of sort of thinking about how we can bring that earlier, whether that is that for example weâre able to sort of more proactively flag when children have you know, more than one visit to a particular type of doctor or something that makes that happen much earlier in the process. So the tooling that we now know works whether itâs whole genome sequencing or something more targeted can be used earlier in the process, or whether for example in our newborn genomes programme we get that evidence that we can look for a broader range of conditions in a screening context right at the beginning of life.
And I think in five to ten years we should be in a substantially different place, weâll know whether or not we think whole genome sequencing should be there but offered for every baby at birth, and we can be much more proactive also when symptoms arise. I would also hope that on the side of therapies and intervention, weâre in a substantially different position and I think, Iâve been amazed the last five years how my level of hope has increased. I believe we should now be in a position in five to ten years where those with a therapy that is potentially there to benefit them, should at least be able to be aware of it and there will be a clear pathway by which either that is available if itâs proven, or thereâs a pathway that we all understand about how that can be trialled. And I think weâre at the beginning of that journey and I now feel itâs a responsibility of ours to work through how we can bring the right pieces into place, we canât prejudge the science, but we can set up the system that makes us be able to respond to it.
Julia: Yeah, I remember Rich when you and I were speaking a number of months ago and maybe you could share the story because you talked about your hope kind of changing over time as a clinician I thought that was really powerful to me.
Rich: Yeah, I remember itâs probably now maybe 15 years ago being asked by a family about what my advice would be to them on the likelihood of there being a treatment for their childâs particular condition being available and in fact they asked me to do it in a way that I sort of provided a formal written report to them that I spent a lot of time thinking about and agonising over and was very honestly you know saying it was highly unlikely that something would become available. If I had to write that same report today it would be very different.
Julia: Thatâs so promising to hear that. I donât know, Ana Lisa, have you had any experiences like that in the past that you feel differently now of how you would approach a family like mine?
Ana Lisa: I think itâs a real balance between having that hope ourselves, sharing that hope with other people and not giving false hope and itâs such a balance when right now more than 95% of rare diseases donât have a treatment and I think thatâs such a difficult position to be in right now. And everything weâve been talking about gives me massive hope for the future and a lot of what weâre pouring our energy and efforts into is both the diagnostics so that weâre not trying to make a puzzle with missing pieces in the dark and thatâs mission-critical, and then the real hope that actually this will drive therapies, which is what we really want for everybody who needs a therapy to have a therapy thatâs effective, whether theyâve got a common condition, a rare condition and thatâs our driving ideal.
So I think Iâm full of hope and optimism and I hope that it will accelerate, thatâs what I really hope, the momentum will build and weâll get to a certain level of knowledge, weâre learning the processes, weâre learning the evidence, weâre learning the collaborative models that are needed to really suddenly explode our ability to treat rare conditions.
Julia: Yeah, you know when Mila was, I guess when I look at newborn screening in the United States and Batten CLN7, which is Milaâs kind of sub-type of her condition is not on newborn screening tests because there is no treatment for it, but the whole genome sequencing that was done for Mila was the data that we got from that was what was needed to create a treatment for her and so itâs an unusual case where she was sequenced and a child and a baby, a newborn in the UK could be sequenced and not only told that they have a disease, so they have time to kind of understand the disease more but also potentially kind of prepare for a treatment that might be in the pipeline, but that data is also going to help scientists and researchers create new treatments that may not be available when that child is born but thatâs the data thatâs needed to create the treatment.
Right now you guys are youâre really at the forefront of solving both halves of the what I consider like a rare condition, you know, global health crisis with tens and hundreds of millions of people that have you know families like mine, like my story sounds unique, it sounds impossible but there are tens of millions of other people like me, like my story sounds unique, it sounds impossible but there is tens of millions of other people like me and so to have the UK kind of leading this effort to solve both halves of the problem, the diagnostic half, you know, what disease does a child have and find it in time and also kind of the treatments, hereâs where weâre headed, and if we donât solve both of those problems then there is no such as access, you know to a better life, so Iâm really grateful for the fact that youâve set a precedent for other countries because now finally there are other countries that are looking towards you and kind of really trying to do the same thing that youâre doing.
Rich: Yeah, well I think we feel weâre uniquely placed; the NHS in the UK and for Genomics England our partnership with the NHS, together with a number of other factors and I think the recognition from government as well as the NHS over a long period that the importance and the power of genomics and the importance of for example, making changes to regulation to get it right mean that itâs something that I think we feel really privileged to be in the position to even be able to ask these big questions.
Julia: yeah, I think the UK is really uniquely suited to have hung their hat on genomics so that the topics youâre taking on are very central, theyâre not kind of on the sideline, they seem whenever Iâm in the UK they say that what Genomics England is doing is at the forefront and in the middle of all the discussions with academics and companies and regulators and government. What do both of you think are the, what are the biggest kind of hurdles we have coming a few years in the newborn programme or you know, any of your other initiatives?
Rich: I guess all of these are big questions and I think we need, itâs back to that sort of point from Ana Lisa sort of balancing the hope and expectation, I think weâre uniquely placed to develop the evidence really clearly and one of the things that we again think is so important is having this conversation in the public about it and developing a shared view, almost you know, it drives policy but itâs also something which I think the whole of society needs to sort of think about how we address and what we want to do collectively. I wouldnât place it as a barrier but I would highlight it as a strength that weâve had and I think weâre hopeful that weâll continue is that long-term commitment in terms of government and the NHS and I think thatâs really powerful in this space to maintain the UKâs position as being able to ask these questions and to show that leadership.
Ana Lisa: And to bring together, we need to work really closely across the ecosystem. So in my mind one of the challenges is if one part is missing then that person is not going to get the treatment and how we keep joining up these really important dots across the whole ecosystem to make sure that most people will one day be able to get a treatment.
Julia: And all those dots honestly, those dots can never even start unless you have a diagnosis and itâs in time. And so there are so many people around the world working on each of those dots that connect a child or a patient to a treatment, but if you canât even be diagnosed or if youâre diagnosed too late, which is what the reality is in the world of rare conditions right, then you know, then itâs a little bit futile to race to a treatment or even think if thatâs possible. So I think the very, very first thing is: can we find children and patients, like can we find children like Mila in time? And I love hearing the word âhopeâ thatâs the word that keeps me going and doing what Iâm doing because if there isnât any hope itâs pretty hard to keep fighting, so Iâm really glad, thank you both for having hope.
Okay, weâll wrap up here. Thank you to Ana Lisa and to Rich for joining me in this conversation today as we shed some light on the challenges you know that those with rare conditions are facing. We touched on the work being carried out across the Genomics ecosystem in the UK to support those living with rare conditions. If youâd like to hear more of this, please subscribe to the G Word on your favourite podcast app. And thank you so much for listening. Iâve been your host, Julia Vitarello. This podcast was edited by Mark Kendrick at Ventoux Digital, and produced by Naimah Callachand.
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In this explainer episode, weâve asked David Bick, Principal Clinician for the Newborn Genomes Programme at Genomics England, to explain more about the Generation Study, in less than 10 minutes.
For more information you can listen to our podcast episode where David discusses the conditions that we will initially look for in the study.
You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel.
If youâve got any questions, or have any other topics youâd like us to explain, feel free to contact us on [email protected].
You can read the transcript below or download it here: What-is-the-generation-study.docx
Naimah: What is the Generation Study? I'm Naimah Callachand, and today I'm joined by David Bick, the principal clinician for the Newborn Genomes Program at Genomics England, and he's going to explain more.
Okay, so first of all, David, please, can you tell me what is the generation study?
David: The Generation Study is a research study organised by Genomics England in partnership with the NHS. So what is the study exactly? We know that children are born every day with treatable genetic conditions. What we want to do in this study is we want to find those children and treat them before they become sick. We know that if we can find these children early in life, we can keep them healthy.
Naimah: Can you tell me a bit about how the study was designed?
David: Yes, this study was designed to look for genetic conditions that are treatable, and we went about looking for which conditions to include through an extensive evaluation that involves specialists, laboratory specialists, the NHS and patients from different support groups. And through this process, we identified more than 200 conditions that are treatable, and we are including those in the study.
Naimah: And David, you mentioned the conditions list there. You can also find an additional podcast on our website where you go into more detail as to why the conditions on that list were chosen initially for the study.
Can you tell me how this fits in with the current newborn screening program?
David: The current newborn screening program looks for a smaller number of conditions, nine conditions. It has been extremely successful and is an extremely important program, and so we're looking to see how our program could be an adjunct to the current screening process.
Naimah: How would people take part in this study?
David: What we're going to do is we're going to ask couples in mid-trimester, in the middle of pregnancy to join in the study, we're going give them a number of opportunities to learn about the study and those that sign up. We plan to obtain cord blood from the placenta after birth. And as you may recall, the placenta is discarded and so this cord blood would normally simply be discarded, but we can take this umbilical cord blood and test it for genes. We expect it to expand to perhaps 40 trusts across the country.
Naimah: And David, the NHS is already under quite a lot of pressure at the minute. What will this study mean for the NHS? What impact will it have?
David: That has been one of the main concerns as we went forward with thinking about the study was to make sure that we did not add additional burden to the NHS. But it's important to realise that the children that we're looking for already have the condition, they're going to become ill.
And our plan is, our hope is that if we can find them before they become ill, we will actually relieve stress on the NHS system. Let me give an example. There is a condition called biotinidase deficiency. Here is a condition where the child who has it, is unable to recycle a vitamin called biotin. Well, biotin is something you can pick up at the health food store, and so these children.
Need to be given extra biotin every day. Very, very inexpensive, very, very safe. But if you don't find these children before they become ill, they can become quite seriously ill. So if we can find these children before they get sick, get them started on this very simple, very inexpensive, very safe medication vitamin. In fact, this will actually save money for the NHS, but also help the NHS function more effectively. And most importantly, to allow parents to have the knowledge that they have done something for their child, which will prevent their child from becoming ill.
Naimah: Some parents might want to know if their child's data is being kept safe. What are you doing to ensure this?
David: Data safety is very important to us. We know that this information is extremely sensitive, and so our data protection is a very high priority. We're controlling very carefully who will have access to the data. There are groups that we do want to work with this data. We want researchers and the pharmaceutical industry to work with this data to improve treatments.
We know that there are many, many genetic conditions for which there is no treatment. Those conditions are not on our panel, and so we're hoping that the information that we learn from these genomes can be used to improve the care of conditions that exist, that are treatable, but most importantly, to find treatments for conditions that are currently not treatable.
And one way that we're doing this is we're going to ask families to stay with us for several years after the program starts. Once we have screened families, we're going to find some that are going to be screened positive, in which case we would look to see whether they have the condition or not, and then go ahead and start treatment.
We also, unfortunately, in a screening situation, we know that we're going to miss some cases, and so again, we want to stay in contact with families so we can know how to improve the testing, but most importantly, to understand how the test works, how screening works using genome and determine whether this makes sense to include all patients that are born in England going forward.
Naimah: And can you just finally tell me where you expect this study to go? In the coming months?
David: What we hope is that one day we'll reach a point where we can find and treat children who have treatable conditions before they get ill. this would really make our healthcare system a real healthcare system. We would find children before they get ill.
In this way we can keep children healthy and help them lead and live their best lives.
Naimah: So that was David Bick explaining âwhat is The Generation Studyâ. You can find out more about the study on our website and if you'd like to follow us on social media, you'll be able to keep up to date with any of the updates.
Thank you for listening.
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In January we saw experts from across the genomics ecosystem, including patients and those with an interest in genomics, gather at the Festival of Genomics - the UK's largest annual life sciences event.
In this episode, our host, Vivienne Parry, Head of Engagement at Genomics England, speaks to Louise Fish, CEO of Genetic Alliance UK, and Professor Matt Brown, Chief Scientific Officer at Genomics England, to discuss the event and emerging future trends in genomics.
In this episode you'll also hear some exciting future advances in genomics research from some eminent speakers at the Festival:
Harold Sneider, Professor of Genetic Epidemiology, University Medical Center Groningen sheds light on the "Identification of methylation markers for Type 2 diabetes up to 10 years before disease onset."Nagy Habib, Professor of Surgery, Imperial College London, delves into "The future of saRNA therapeutics and its potential for treatment". Lennard Lee, National Clinical Advisor on innovation and cancer vaccines, presents his perspectives on "The Future of Cancer Vaccines," offering a glimpse into the promising advancements in this critical field."The scientific breakthroughs that are being made are absolutely incredible and theyâre really exciting, but from the point of someone living with a genetic condition, what they want to see is those scientific breakthroughs making a real difference in the clinics...For some conditions, itâs about treatments, but itâs also about being able to get a diagnosis faster, to be able to understand what condition is impacting on you, how it might affect you over your lifetime and your wider family, and to be able to work with NHS services to understand and plan for the care and treatment that youâll need throughout your lifetime."
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/Insights-from-the-Festival-of-Genomics.docx
Vivienne Parry: Hello and welcome to the G Word.
Vivienne Parry: The Festival of Genomics is the UKâs biggest genomics event, and itâs become an essential part of our year. Itâs free for 90% of its delegates, itâs in person, and with more than 5,000 people expected, itâs now so big that itâs had to move to ExCelâs cavernous Dockland Halls. Itâs the place to hear top science and to spot new trends, but actually for me the joy of the festival is the people you meet. Of course, itâs great to catch up with old friends, but itâs the new collaborations sparked by random encounters at the festival which I think are the lifeblood of the genomics ecosystem, and everyone with an interest in genomics is here, patients, clinicians from the NHS, researchers, industry, policymakers, and the G Word.
What we thought weâd do is bring you a flavour of this great event from the floor of the ExCel halls, and give you a quick soundbite from three of the speakers that we felt best exemplify the future of genomics. With me to discuss the event and future trends in genomics, Professor Matt Brown, Genomic Englandâs chief scientific officer, and Louise Fish, CEO of the Genetic Alliance UK, which as its name suggests, is an alliance of over 200 organisations reflecting the needs and concerns of those affected by genetic conditions. My nameâs Vivienne Parry, Iâm head of public engagement at Genomics England, and Iâm delighted to be your host for todayâs pod from the Festival of Genomics. Welcome to you both. So, letâs start with you, Matt. How important is the Festival of Genomics for genomics in the UK?
Matt Brown: Well, the Festival of Genomics has become a really key meeting for the genomics community in the UK, and I think increasingly in Europe as well. Itâs a really large, high quality event that brings together commercial and academic and biotech companies in the one forum, and I think itâs a really exciting programme.
Vivienne Parry: And of course, Louise, itâs open to patients as well, which makes it an unusual event.
Louise Fish: Absolutely, and itâs brilliant to have patients and families here. So, people living with genetic conditions clearly need to be part of the debate when weâre talking about developing new services, and developing new treatments and diagnostics, so itâs absolutely fantastic to be able to come together in one room with people from the NHS and the broader sector.
Vivienne Parry: And itâs grown enormously, and I guess that reflects, as much as anything else, just how exciting genomics is. Matt, Iâm going to pin you to the ground [laughter] and say, why is it so exciting in genomics at the moment?
Matt Brown: Look, the fieldâs really hitting its tracks. Weâre seeing advances in technology, analytics, application in the clinical space, and of course booming commercial activity associated with that. But from a situation ten years ago, where we had research capability for using genomics to assist in diagnosis and cancer profiling, now weâre in a situation where we have multiple different approaches to assist with both of those things, transcriptomics, proteomics, spatial, single cell methods, optical mapping, a whole monopoly of different technologies that have developed out of the research world but are pretty close to being ready for clinical application. Of course, in analytics, the rise of AI and the potential that has for improving interpretation of genomes and improving personalised medicine prediction in cancers and in multivariant data, those are absolutely massive things. But aligned to that, thereâs also, you know, the growing worldwide application of genomics in clinical spaces, of course led through the UK and the NHS Genomic Medical Service, which has really shown the way for the world about how this might make a difference.
Vivienne Parry: And Louise, thatâs the really exciting thing is weâre now seeing not just talk about therapies, we are seeing the therapies for rare disease actually going into clinical trials and into services even.
Louise Fish: Yeah, absolutely, and thatâs why people living with genetic conditions and their families want to see the change. The scientific breakthroughs that are being made are absolutely incredible and theyâre really exciting, but from the point of someone living with a genetic condition, what they want to see is those scientific breakthroughs making a real difference in the clinics. And thatâs sometimes about treatments, you know. For some conditions, itâs about treatments, but itâs also about being able to get a diagnosis faster, to be able to understand what condition is impacting on you, how it might affect you over your lifetime and your wider family, and to be able to work with NHS services to understand and plan for the care and treatment that youâll need throughout your lifetime. So, treatmentâs one part of it, but actually that ability to better understand what the future will hold for you, and to plan ahead for the care and support that you will need to live your life to the full is what really excites people living with genetic conditions and their families.
Vivienne Parry: Now, letâs hear the first of our three clips. The programme is absolutely vast, but these were three presentations that we just thought were terrific. Letâs hear the first one.
Nagy Habib: My name is Professor Nagy Habib. Iâm a consultant surgeon at Hammersmith Hospital, Imperial College, London. We are going through a very exciting time, where we know what is the problem with the diseases, and so far we couldnât do anything about it, but suddenly the door is opening and it all came with the RNA vaccine, because we had to go very fast to get a vaccine for covid, to protect the population, and that pushed the science to go very fast, and now we can apply it to other areas apart from covid, like cancer and rare genetic diseases. And these therapeutics are what you and I and everybody else have received during vaccination. There has been six billion injections around the world, so you can imagine that everybody had an RNA injection. And RNA is that molecule between our genome, the DNA, and the protein. For anything to happen in our body, it requires the protein, but there must be an RNA in between. In the past, it was all about DNA, but now it is RNA. Why canât we get a vaccine against cancer?
And so now the field is growing very fast for a vaccine for cancer. Now, the way we think about it is that we can have an injection so that we donât develop cancer of the prostate or cancer of the breast and so on, but in actual fact today what we can say is that if we take out a tumour with surgery, and we can take the RNA from the tumour and inject it in the patient, the early clinical trials tell us that this might work, and to stop the tumour coming back. It is very important to make sure that, once the tumour is out, it doesnât come back. And I think there is hope that we can have RNA vaccines in cancer. Now, to treat cancer without surgery, still we have some way to go, but again, now we know that the problem with cancer is that some of our immune cells that are there to defend us from cancer, they change their mind and suddenly they collaborate with the enemy. So instead of helping us, they are destroying our immune system, and we are developing drugs that can stop that from happening to our immune systems.
Now, when you really think about what are the diseases that kill people, cancer is definitely very high up. The second one, not in a particular order, but cardiovascular system, we get heart attacks and we die from heart failure, or we get stroke and we die from stroke, and thatâs because we eat too much. The food is very tasty [laughter]. So, now we have injections, and the injection can make us lose weight, and we lose weight very fast. The problem is again itâs very expensive. Who can afford ÂŁ600 a week? And when you stop the injection, you put on weight again. So, now we are working again with RNA, and we have found a way where you inject only once every six months.
And then the final thing, which is really the dream of everybody, is to stop Alzheimerâs disease. So, Alzheimerâs disease, as we get old, there are toxic materials that are accumulating in our brain cells, and only this year weâve got two drugs coming along that can help stopping Alzheimerâs disease at an early stage. Now, what we need to do is to bring that it works on all types, even the advance type of Alzheimerâs disease, and now there are [inaudible 0:09:26] where we can take it from the nose. So, you inhale it from the nose and it goes straight to the brain, because there is sort of a motorway that connects the roof of the nose with the base of the brain, which is very simple. It doesnât even need an injection in the arm vein. So, itâs all very, very exciting.
Vivienne Parry: That is so fascinating. Itâs real future casting. Matt, I mean, I say itâs future casting, but tell me a bit about the Rare Therapies Launchpad, because, you know, that picks up some of what Nagy has outlined.
Matt Brown: Yeah, so DNA and RNA therapeutics are absolutely booming, and thatâs one of the big excitements is that weâre not only being able to diagnose people, but weâre coming up with new ways of actually providing treatments for patients with rare diseases and cancers through nucleic acid therapeutics. For rare diseases, the type of clinical trials that are involved are really quite different, and you canât just basically translate what was used for common diseases into the rare disease space. It just doesnât work, and thatâs really held back the field a lot. So, to try and enable rare therapies to actually make that leap from a research setting into actual clinical practice, Genomics England, in partnership with the Medical Health Regulatory Authority and others, have set up a Rare Therapies Launchpad, to provide an end to end solution for people to be able to run clinical trials for rare and ultra rare diseases, particularly focusing on nucleic acid therapies, and linking that with both the regulatory authorities and health funding authorities so that we can get these ultimately into clinical practice. I think we need these sorts of initiatives so that we donât continue to see rare therapies falling over because theyâre being assessed and made to go through the hurdles that common therapies do nowadays.
Vivienne Parry: So Louise, we really are in the area of what people call N of 1 medicines.
Louise Fish: Yeah, absolutely. So, these are medicines that are made specifically for one person and will help that one person, and obviously that brings a whole heap of possibilities for people living with genetic conditions, but also a load of challenges that we understand for decision makers within the MHRA and NICE and the NHS. And so I think there are some real challenges that weâre really aware of from the decisions that are already being made by those decision making authorities about treatment. Obviously, putting it at the most basic level, you donât have the same evidence base for treatment thatâs just available for one person that you do from a clinical trial, where thousands of people will have taken part in a trial to understand how it affects a whole host of people.
So, we know that the decision making bodies are going to need to take a different approach to evidence, so are going to need to be willing to look at evidence that is just from a trial involving one person. Theyâre going to need to be able to extrapolate the benefits of that treatment across someoneâs lifetime, and that can be challenging, and weâve seen that before in rare disease medicines and the new treatments that have come along in recent years. So, there are definitely some challenges, and weâre really glad to see those challenges being acknowledged upfront by Genomics England, the MHRA and others, and being debated and discussed, and trying to find solution now rather than waiting for those treatments to come along later, and then trying to retrofit and decide how to manage them. So, itâs great to see this debate taking place early, and weâre really keen to make sure that the voices of people living with rare conditions and their families are part of that discussion.
Vivienne Parry: And the really cheering thing that weâre hearing from Professor Habib is that he thinks that the cost is going to be much less, because some of these things, you know, have million pound price tickets, so to have something that will be cheap is really going to be I think the gamechanger.
Louise Fish: One of the challenges with that is understanding the lifetime costs of someone living with a genetic condition and all of the complexities that are involved, and not just the medical care that they need, but the social care and the wraparound care that theyâll need, the extra support from schools and colleges, the extra support from employers if theyâre able to go in employment. So, I think weâre constantly trying to help the government and decision makers have a better understanding that those lifetime costs of living with a genetic condition are the things that should be taken into account when theyâre making decisions about a new treatment that could be totally game changing for someoneâs health and their future.
Vivienne Parry: Cheaper treatments on the way, Matt?
Matt Brown: So, I think we absolutely need to work on reducing the costs of these treatments, because at the moment the costs are so high that, were we to extrapolate that out to try and treat the thousands to tens of thousands of different rare diseases that there are out there, we couldnât possibly afford it. I think itâs very promising that we will get cheaper treatments. This might come about through reducing the development costs, in particular reducing the clinical trial programmes, and the level of safety and efficacy evidence that you require before you can actually make these treatments available. I think that will make a massive difference, if we can simplify that.
And another thing is, by better collaboration between the different rare disease communities and genetic medical services around the world, to make sure that what might be an N equals 1 condition in the United Kingdom, when you consider it around the world, might actually be an N equals 100 people, and then basically the cost per patient drops substantially. To achieve that, we need much better coordination between the national genomic medical services.
Vivienne Parry: At the end there, you heard talk of using RNA therapies for obesity and Alzheimerâs, and we principally talk, particularly in Genomics England, not just about cancer and rare disease. But I wanted to present to you another presentation, which I just thought was extraordinary, which comes from the Netherlands, and itâs about picking up signs of diabetes using genomics ten years in advance. Just listen to this.
Harold Sneider: Hi, Iâm Harold Sneider, Iâm a genetic epidemiologist working at the University Medical Centre in Groningen in the Netherlands, and my focus is on cardiometabolic disease, and I have a great interest in hypertension, for example, obesity, but also type two diabetes. So, one of my major interests is to try and identify genes for common complex, mostly cardiometabolic diseases, so our approach is to do genome-wide association studies using genetics, but also epigenetics. And epigenetics can be screened for so-called methylation markers, and those methylation markers have an effect on expression of the genes, and we can look at this all over the genome. Then a very interesting question came up, whether these types of epigenetic signals or methylation markers could actually be used to predict disease in people that are still healthy.
So, the goal of this type of work always consists of two parts. First, itâs that we try to find out which genes are highlighted by these DNA methylation markers, because they are located at certain positions on the genome, so we know which genes are involved in those regions and we can learn more about the underlying biological mechanisms that play a role in the development of the disease. Because we found those signals up to ten years before the disease occurred, so that tells us something about changes that already happen at an early stage. Itâs like an early detection mechanism. At the same time, a combination of these markers together lets you calculate whatâs called a methylation score that can be used for the prediction of the disease, and the ultimate goal here is that even in healthy individuals, when you have those measurements, you can calculate such a score to improve the prediction and identify people with a higher probability to develop such a disease. I definitely think we can apply this general approach also to other â for example, cardiometabolic diseases, such as coronary artery disease or also hypertension.
Vivienne Parry: Harold Sneider there from Groningen. And extraordinary, the idea that you might be able to pick up not just diabetes perhaps ten years in advance, but also he was talking about potential for other lifestyle diseases, like cardiovascular disease, for instance. What are your thoughts about that, Matt?
Matt Brown: Look, I think itâs always been an aspiration of the clinical community to move treatments from treating patients with established disease to actually working in really early or preclinical spaces, where youâve got a much better chance of preventing end organ damage, and secondly youâve got a much better chance of actually inducing remissions or potentially actually curing diseases. And I think not just in diabetes, but also in a range of immune mediated diseases, thereâs pretty good evidence now that you can, by intervening early, really make a massive difference to the natural history of diseases, and new methods are coming about to identify those patients, be it polygenic risk scores or other biomarkers, to enable us to sort of flip the approach of medicine from being reactive to pre-emptive.
Vivienne Parry: And rare conditions, as they do so often, Louise, are leading the way in understanding the issues, which will then spill out into a much wider area of the population.
Louise Fish: Yeah, absolutely, and rare conditions obviously is the space that we work in. So, Genetic Alliance UK, as you say, is an alliance of around 230 charities that support people largely with rare genetic conditions, and many of those charities are condition specific or look after groups of conditions, like metabolic rare diseases. So, thatâs the kind of space that we come from, and obviously in our space, the excitement is around the work that weâre doing with Genomics England around the Generation Study, and trying to use that to understand whether it's possible to screen babies to understand whether they have a rare genetic condition, and if so to identify that condition and intervene early. And again, excitingly, thatâs not just about treatment, itâs about whether thereâs a way of helping that child and their family, if you can identify very early to help really improve their lifestyle choices. And one of the best examples we have is identifying children with brittle bone disease, where if you pick them up through screening, youâd be able to teach their parents to handle them safely, so they didnât have breaks in their bones as babies, which is what we see now.
So from our perspective, itâs obviously different to the polygenic risk scoring, but again itâs that idea of using genomics as a way of identifying conditions very early, and intervening before signs and symptoms start, to try and improve the life chances of the person living with that condition, and help their wider family to help them, which is really exciting from our perspective.
Vivienne Parry: But the experience and knowledge that youâve gained as rare disease organisations actually is enormously valuable to other people. I mean, rare has always been at the forefront. I mean, in cancer, for example, it was chronic myeloid leukaemia, which was a rare cancer, that kind of unlocked cancer targeted treatments for everybody else. And it always seems to me that rare is at the forefront. Although itâs often seen to be behind, it actually is the key to unlocking so many other things, and the experiences that you have all had are so valuable for much wider populations.
Louise Fish: Yeah, absolutely, and one of the reasons we run Genetic Alliance UK is so our member organisations can learn from one another, âcos thereâs always one of the rare patient organisations which is surging ahead in a particular space, doing something really exciting, doing something really new, and we try and make sure that our members can learn from one another and donât have to kind of reinvent that wheel. But I know that spills out into the wider cancer space and beyond, which is fantastic.
Vivienne Parry: And Louise, do you think there are particular conditions which, if I can put it like this, are on a roll at the moment, where genomics is really advancing fast for them?
Louise Fish: Oh goodness, thatâs a really good question. There are lots of conditions where genomics is making a significant difference really quickly. For us, I think we go back to the Generation Study, and at the moment we only screen in this country for nine conditions, soon to be ten with the addition of a new condition, but the Generation Studyâs looking at 200 conditions and whether itâs possible to screen for them. And for all of those 200 conditions, itâs a really exciting opportunity to see if we can learn more, both about the potential to understand and develop treatments early, but also just about the chance to understand the natural history of that condition so much earlier than we do at the moment. And I think thatâs it, itâs that understanding of the natural history of the condition really early, and understanding how a family can be helped through all the aspects of the condition, which is giving people most excitement, I think, alongside the potential to develop treatments.
And I know we talk about treatments a lot, but at the moment only five percent of rare diseases have a condition specific treatment available, so we really try and balance, within Genetic Alliance UK, that hope for the small number of conditions that do have treatments, which is really exciting, or have treatments in development, and actually making sure that the scientific breakthroughs in genomics are something that all conditions can benefit from, whether thereâs a treatment or not. The potential for early identification of people with a condition, understanding the natural history better, and wrapping a package of support and care around people that is not just about a drug itself, is really important to us and to all of our members.
Vivienne Parry: Matt, are you seeing any particular areas where thereâs a really rapid success?
Matt Brown: Look, I think there have been some absolute standout successes in nucleic acid therapies in recent years. So, one is the treatment of familial hypercholesterolemia, with siRNAs for PCSK9, so the Inclisiran type approach, which has absolutely revolutionised management of that disease. In recent times, Iâd highlight, for example, the treatment of sickle cell disease, an absolutely massive global problem, and now weâve got a therapy which can really control sickling crisis and make a big difference to a disease which isnât just a disease of developed countries, in fact itâs particularly a disease of Africa, of course. On a global level, thatâs just going to have a huge effect.
But I think, yeah, I just would like to come back to that comment you made about things starting with rare diseases. So, in genomics, rare disease genomics has taught us a heck of a lot about what drives common diseases as well, and to my mind, gold dust for drug development companies is where you have genes that are associated with both rare and common forms of the same type of disease. And that tells you that basically youâre very likely, through your treatment, to be able to actually influence the disease, and that it will influence a large proportion of patients with the disease. So, Iâm really enjoying seeing this division between rare diseases and common diseases broken down a little bit, and a lot more learning in therapies going from one to the other.
Vivienne Parry: Letâs move to a completely different area, one thatâs very important to Genomics England and less important, Louise, at the Genetic Alliance UK, which is cancer. Weâre going to hear from Lennard Lee about cancer vaccine.
Lennard Lee: Iâm Dr Lennard Lee, Iâm a medical oncologist, so I practice as an NHS doctor, treating cancer, and Iâm an associate professor at the University of Oxford. Weâve come to a position whereby vaccines can be developed quicker than anyone thought. In the last few years, weâve realised that the technology has moved on rapidly, MRNA technology, and you can make vaccines and update them really, really quickly. Weâve now come to a situation where vaccines can be made against cancer, and this is where genomics is really starting to supercharge this technology. If you can sequence a cancer then what weâre finding now is that the technology now exists for you to print off an MRNA vaccine for that patient, a truly personalised product. And itâs amazing because the genetic basis of the cancer, what the genomics sequencing shows then becomes a vaccine itself. The vaccine is designed based on that sequence, and thatâs why genomics has really supercharged this field of vaccinations for cancer.
One of the possible things we just need to clarify and be aware of is that when people talk about cancer vaccines, they mean a number of things. Ultimately, what it involves is getting a new treatment for people with cancer, because itâs based on their genetic sequence, so itâs used to treat people with cancer. The futureâs an exciting one, truly personalised medicine based on genomics. Genomics is going through so many different phases in the field of cancer. Firstly, we were starting to understand why cancer happened and what patients outcomes were. The second phase started to kick off where genomics would help patients select the right drugs at the right time for them, which is amazing. And now weâve entered the final evolution of genomics, where it now becomes the actual drugs that we treat people with. And cancer vaccine is one of the first potential areas where genomics will start to form the basis of the treatments going ahead. In five yearsâ time, weâre going to know if it works or not, where an individual vaccine based on the genomic abnormality seen in that cancer is going to give better outcomes for patients than an off the shelf product.
We know that every cancerâs different, so genomics has showed us this, but all of a sudden that sequence could become that vaccine, which then primes that immune system, truly personalised therapy. And it is so exciting that weâre going to be talking about this in this festival, and itâs being driven as from the UK, which has got so much strength in terms of genomic capabilities as weâre developing vaccines.
Vivienne Parry: So Lennard Lee there, absolutely confident of the importance of cancer vaccines. Matt, what are your thoughts on that?
Matt Brown: I think itâs a tremendously exciting field. The early data on cancer vaccines with melanoma, for example, showed that for a cancer which previously had been resistant to virtually all of our approaches, is actually quite responsive to novel cancer vaccine approaches. We are yet to see across what diversity of cancers this is actually going to work, so thereâs clearly a huge clinical trial programme thatâs going to be required to drive this, and the UK is playing a really central role through the Cancer Vaccines Launchpad that Lennardâs involved with running, in creating the evidence base about whether these are going to achieve the promise that they hold.
I also think that theyâve got a lot of possibility for inherited cancer types. For example, I think the programmeâs looking at cancer vaccines for Lynch syndrome, to try and prevent colorectal cancer in that group of patients. So, I think theyâve got lots and lots of opportunities, and itâs nice to see something positive actually coming out of the pandemic like this, for what was a pretty bleak episode worldwide otherwise.
Vivienne Parry: They are a small part, I know, of your organisation, Louise, but in some ways, those people with inherited cancers in their families are seeing the benefits of genomics on both sides, both in that earlier diagnosis, picking up right from the very beginning, and of course in the promise of these new treatments.
Louise Fish: Yeah, absolutely, and youâre right, itâs a small part of our remit. We do have some organisations in our membership who specifically support people with rare inherited cancers, and we work very closely with an organisation called Cancer 52, who also represent organisations with rare cancers. Iâll just give them a quick shoutout in case anyone listening is not aware of them and their amazing work. But youâre right, I think there are a couple of things going on that are really exciting in the cancer space. Itâs that ability to better understand why some people are likely to inherit cancers, how that pattern works within families, and to support those families and help them understand like the risk that they have, and to make informed decisions about their own treatment and care in the future. And also about whether they want to have children, and if they do want to have children, kind of how they want to approach that to try and reduce the risk of passing on that heritability. So, thatâs a really important part for everybody. I think thereâs also potential to develop new treatments, which is absolutely amazing and really exciting, and it is really exciting to hear about the potential for cancer vaccines.
The other area where I think people living with inherited cancers are interested to find out more is what impact it might have on better understanding which treatments will work for which people. And we know, for example, that there are some cancer treatments that only work for one in four people with that particular kind of cancer, but itâs been really hard to understand why thatâs the case. And I think the potential for genomics to identify which people could benefit from a particular cancer treatment would have two huge benefits. A, cancer treatments, many of them are really horrible, you know. Theyâre horrible things to go through, and if you had a better confidence that a particular treatment was going to work for you because of your genetic makeup, that would make you a lot more confident about deciding to try that treatment, and taking on board the side effects of the treatment and how itâs going to impact on you.
That would also obviously massively impact on the cost effectiveness of that treatment. At the moment, we might give it to four people and only one of them would benefit, but youâre paying for the cost of giving it to all four people. If you could identify in advance which people were more likely to benefit then youâd give it to fewer people, theyâd be more likely to benefit, and the cost would come down. So, I think that there is real potential in this field of genetics and genomics to help in all kinds of ways that people living with these conditions are really excited to see and explore.
Vivienne Parry: So Matt there, itâs not of course simply about identifying, you know, what the cancer is like and its genomic makeup, but actually itâs that wider field of pharmacogenomics, which is a big feature of the programme at the Festival of Genomics this year. And weâre very much involved in that, arenât we?
Matt Brown: Yeah, we are. So, pharmacogenomics is one of those areas where genomics is about to make a big difference in clinical practice. What weâre hoping to get to is the point where we have people who are not yet treated with a medication actually already have the genetic profiling done, so that when they go to a general practitioner or a physician and be prescribed a medication, the data will already be there to say what the appropriate dose should be, and whether theyâre at risk of getting adverse reactions to those medications, so we could avoid them or use alternate medications. So, that sort of pre-emptive pharmacogenomics is just over the horizon, and if we can achieve that, weâre going to significantly improve patient care and reduce the risk of adverse drug reactions, which are a major cause of morbidity and hospital admissions not just in the UK but worldwide.
Vivienne Parry: So Matt, perfect segue into our next question, which was, youâve already identified one area which you think is going to be big in the next few years. Youâre both absolutely in the centre of the genomics ecosystem. What do you think weâre going to be seeing at next yearâs Festival of Genomics? What do you think is going to be the big thing thatâs coming up on the inside rail?
Matt Brown: So look, Iâd like to say what I thinkâs going to be in next year and what I thinkâs going to be in ten years. Next year, I think the big things are going to be advances in AI and genomic analytics. Thatâs really ramping up fast, and I think weâre going to see it in clinical implementation a lot more next year. I think the cancer therapy vaccines are going to be really big next year, as are nucleic acid therapies. Multiomics for rare disease diagnosis and cancer personalised medicine, I think is also ramping up very fast. In ten yearsâ time, the two areas that weâve not discussed so far where I think genomics is going to make a big difference are going to be in infectious diseases and in pathology services. In infectious diseases, genomics I think has a fair chance of replacing to a large extent culture based practice, or serology based diagnosis of infectious diseases, which will be done by sequencing instead. And that will be a massive change to the practice there, because youâll be able to rapidly work out, even if people have been treated with antibiotics already, what the infections are and what the likely treatment responses are going to be.
Louise Fish: So from my perspective, next year what I hope to see is people getting just as excited about the differences that some of the technology we hear about this year are actually making when theyâre being applied in clinical practice. So I think from my perspective, itâs all about that move from being excited about the science to seeing people just as excited about the difference that science is actually making when itâs benefiting people living with rare conditions and their families through clinics across the UK and the NHS. Next year, Iâd like to hear that excitement when people are talking about how itâs actually affecting real lives. In ten yearsâ time, I hope weâll be talking about the massive difference that some of the amazing techniques weâve heard about here this year have made to the lives of people living with genetic and rare conditions.
So, you know, in ten yearsâ time, I hope that some of the treatments and the opportunities and the tests we hear about today, we can see how theyâve affected the natural history of the condition across ten years of lives, and that we can really see that people are living their lives to the full as a result of the fantastic technological breakthroughs that weâre hearing about today.
Vivienne Parry: Fantastic. Itâs been great to talk to you both, and it has been a fantastic festival.
Vivienne Parry: So, thank you to you again, and also thank you to Frontline Genomics, who organised the Festival of Genomics, because it really has been a wonderful, wonderful event. And if youâre interested in things genomic, you can subscribe to the G Word on your favourite podcast app, and if youâre new to our podcast, and we always welcome our new listeners, do check out our back catalogue. Youâll find itâs really extensive. Thereâs a wonderful set of genomic listening available to you, in which even spatial transcriptomics gets explained. Iâve been your host, Vivienne Parry. This podcast was edited by Mark Kendrick at Ventoux Digital, and produced by Naimah Callachand, and it's very good to have had you with us. Bye for now, and hope to see you at the Festival of Genomics next year.
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In this explainer episode, weâve asked Ana Lisa Tavares, Clinical Lead for rare disease research at Genomics England, to explain what a rare condition is, in less than 10 minutes.
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 youâve got any questions, or have any other topics youâd like us to explain, feel free to contact us on [email protected].
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/What-is-a-rare-condition.docx
Naimah: What is a rare condition? Today Iâm joined by Ana Lisa Tavares, Clinical Lead for rare disease research at Genomics England, and sheâs going to explain more.
Ana Lisa: There are thousands of rare conditions. I hesitate to say a number as weâre learning all the time, so this keeps changing. There are estimated to be perhaps around 10,000 different rare conditions, as an order of magnitude. Many rare conditions start in childhood, 75% or three quarters affect children. A little over 10% affect adults, only adults, and some, around 20% can start in children or adults.
Naimah: So, what makes a condition rare?
Ana Lisa: A rare condition can be defined as affecting less than one in 2,000 people in the general population. This is a definition thatâs used in Europe. Different parts of the world use slightly different numbers and definitions, so for example, the number of people with a rare condition living in that country, there isnât one single universal definition.
The important part I think is that this is a practical way to help shine a spotlight on rare conditions, which collectively affect a lot of people, and the particular challenges in making diagnoses and finding treatments for rare conditions. So together, itâs estimated 7% of people are affected by a rare disease in their lifetime, or one in 17, so that means that there are 3 and a half million people in the UK affected by a rare disease, and in the world, probably somewhere between 250 to 450 million people, so perhaps 350 million people, a really huge number.
When you look into these numbers, there are rare conditions that are much more common than others. So, 80% of people with a rare condition have one of the 150 most commonly occurring rare conditions. Cystic fibrosis would be an example that many people will have heard of, and if you look at those numbers from a different angle, 85% of rare conditions affect less than one in a million people, so are very rare, and itâs important to bring together these different voices to solve some of the common challenges.
Naimah: Can you explain to me how these differ from more common conditions?
Ana Lisa: The simplest answer is that they are defined by the frequency, so how often they happen in the general population, and one reason for grouping together thousands of rare conditions is to highlight some of the particular challenges. This includes delays in getting a correct diagnosis that can often take years, an increased chance of a misdiagnosis before getting to an accurate diagnosis, and treatment challenges, as 95% of rare conditions donât have a specific treatment. This is a very good question, and I would like to note that itâs also an artificial distinction to some extent. So, human conditions have a range of underlying causes that can be broadly grouped together, including genetic and environmental, such as a viral infection.
However, it gets complicated, for example, a proportion of common conditions that may have many different causes will have a genetic component, so for example causing an early onset familial form of a condition, such as diabetes. And in fact, genetic causes may give or can give the clue or the key thatâs necessary to develop a new drug therapy that can then help many people with the condition, so those that may have a rare genetic cause and those that have a more common cause, such as for high cholesterol.
So, one other way that rare and common conditions can differ, not just based on frequency, is the causes of those rare conditions and common conditions. Iâll start by saying that there are lots of rare conditions that arenât genetic, and there are common conditions that do have a genetic basis, so none of these observations are absolute, but thereâs a spectrum of different causes for rare and common conditions. So, I would say there are more rare conditions that are caused by a single genetic cause, and there are more common conditions that might be caused by many very small genetic effects acting together, and also many different environmental causes.
Naimah: So, are rare conditions always genetic?
Ana Lisa: The short answer is no. Many rare conditions do have a genetic cause, perhaps 70 to 80% of rare conditions, so if you had 10 people with different rare conditions together in a room, the chances are that 8 of them will have a genetic component to their rare condition. And when we talk about genetic causes, these can of course be very varied, from a single letter change in the DNA code to an extra chromosome with several hundred genes. Rare conditions include ones without any known genetic cause, so for example some rare infectious diseases and some rare cancers. And I think itâs important to say that thereâs a lot that we collectively donât know yet about rare conditions, so our understanding is incomplete and imperfect, and thereâs still a huge amount to understand.
Naimah: And it would be good to understand what challenges patients with rare conditions might face.
Ana Lisa: There are many challenges in achieving an accurate diagnosis, getting well organised, coordinated care, and the fact that 95% of rare conditions donât have a specific treatment. Thereâs a big impact on emotional wellbeing for those with rare conditions and their parents and carers. Genomic Alliance did a survey showing that 88% of those with a rare condition felt emotionally exhausted from having their rare condition, and there are big impacts on other aspects, such as education, employment, etc.
Naimah: And what do you think the future looks like for the treatment of patients with rare conditions?
Ana Lisa: So, this is a huge question with many answers. I think key is coordinated care, and Iâm personally really excited about the potential for new rare therapies to be made for particular types of genetic causes that perhaps one day could be modified to treat many different types of rare conditions. To me, this would be incredibly powerful and would be a dream to transform therapies for rare conditions.
Naimah: That was Ana Lisa Tavares explaining what a rare condition is. Iâve been your host, Naimah Callachand, and if you want to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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On this episode of the G Word, we delve into the promising advances that artificial intelligence (AI) brings to the world of genomics, exploring its potential to revolutionise patient care. Our guests discuss public perspectives on AI in genomics and address the ethical complexities that arise in this rapidly evolving field. Gain valuable insights into the future landscape of genomics and AI, as our experts discuss what to expect on the horizon.
Our host Natalie Banner, Director of Ethics at Genomics England, is joined by Ismael Kherroubi GarcĂa, member of the Participant Panel and Ethics Advisory Committee at Genomics England, and Francisco Azuaje, Director of Bioinformatics at Genomics England.
âSo, AI is already driving the development of personalised medicine for both research and healthcare purposes. [...] In the context of healthcare, we are talking about AI tools that can support the prioritisation, the ranking of genomic variants. To allow clinicians to make more accurate and faster diagnosis.â
You can read the transcript below or download it here: Can-Artificial-Intelligence-accelerate-the-impact-of-genomics.docx
Natalie Banner: Hello, and welcome to the G Word. In the past few years, artificial intelligence, or AI as a shorthand, has taken centre stage in the headlines. Sometimes for really exciting, positive reasons about the potential to drive improvements for society, and sometimes because of its potential risks and harms. These discussions and stories can sometimes seem like they're straight out of science fiction. There are a lot of questions, excitement, concerns about the societal impact of AI, so not just looking at individual patients, but that broader what does this mean for society?
Ismael Kherroubi GarcĂa: My somewhat hot take is that AI only accelerates societal impacts that genomics research and healthcare can have. So the impacts, of course, will be diverse and complex and quite widespread, especially given the quite nuance and sometimes difficult to understand areas of genomics and artificial intelligence. But the key takeaway from what I want to say is that it only accelerates the impacts of genomics and healthcare. So if we take genomics research to promote human flourishing, ideally, artificial intelligence will also only help further human flourishing. Conversely, applying artificial intelligence tools to genomics research can help perpetuate certain stereotypes and related harms.
Natalie Banner: My name is Natalie Banner, and I'm the Director of Ethics at Genomics England. On today's episode I'm joined by Ismael Kherroubi GarcĂa, member of the Participant Panel, and Ethics Advisory Committee at Genomics England. And Francisco Azuaje, Director of Bioinformatics at Genomics England. In today's episode we aim to cut through the hype and hyperbole and explore the real possibilities for AI within the domain of genomics and healthcare. We'll look at how AI tools and techniques have been used to date, and what the future holds, considering both the benefits and challenges faced in the genomics ecosystem. If you enjoy today's episode, we'd love your support. Please like, share, and rate us on wherever you listen to your podcasts.
AI is in the news an awful lot, and not always for good reasons. There are many big and small tech companies that are exploring the use of AI in all walks of life, from finance to retail, to healthcare. And it's not always clear what AI means in these contexts, where it actually has the potential to really help people, drive improvements to healthcare and society, for example. But there are some exciting stories, so recently, Genomics England undertook a collaboration with DeepMind on their AlphaMissense tool, and that sought to classify the effects of 71 million missense mutations in the human genome. So it could process data at a scale and a speed far faster than any human has ever been able to before. So there's an awful lot of exciting work going on in AI, but we should emphasise that although some of this technology is really cutting edge, a lot of the techniques that are being used and talked about in AI, have actually been around for quite a long time. So Francisco, if I could start with you, can you help us understand what artificial intelligence, AI really is in the context of genomics? And maybe explain to us the difference between AI and machine learning, and how they relate to one another?
Francisco Azuaje: Sure, Natalie. AI involves the creation of computer systems capable of performing tasks that typically require human intelligence, such as understanding natural language, recognising patterns in big data sets, and making decisions. Now, machine learning is the most successful technology within the field of AI, but machine learning focuses on the use of algorithms that allow computers to learn from the data and make predictions about the data without the need for explicit programming for each task or application.
Natalie Banner: Ismael, perhaps I can turn to you. What do you see as the primary motivations or reasons for incorporating AI into genomics research and, indeed, into healthcare?
Ismael Kherroubi GarcĂa: So I think it's already been mentioned and focusing on genomics research because challenges, the enormous amounts of data that are required to shift through and analyse and get insights from. So one number that's worth just mentioning is that the human genome is made up of 3.2 billion base pairs, As with the Ts and the Gs with the Cs in our DNA. And one way to put that 3.2 billion, with a B, in terms we might understand, is to say that to list all of those letters we would have to be typing 60 words a minute, eight hours a day for about 50 years, that's how enormous just one human's genome is. And I kept looking for other ways of depicting just how enormous this data set is, and it turns out if you uncoil those strands that we usually see depicted when talking about DNA, if we uncoil them for one person, we would have a string about 67 billion, again with a B, miles long for each person, that's roughly 150,000 round trips to the moon. So, again, this is just one person, those numbers are enormous.
It's also worth considering the role technology has had to play in enabling genomic research. So if we look back at maybe a very significant catalyst for genomics research, the human genome project which started in 1990, they took 13 years to sequence one human genome. Now, what we're talking about is estimating that by 2025 genomic-related data will be up to 40 exabytes of data. Now I didn't even know what an exabyte even was before this podcast, so I did look it up, that's about a billion gigabytes, I definitely don't know how to even begin to imagine what 40 exabytes even means. Bringing it a bit closer to home, I try to figure out how many copies of Doctor Who we would need to make 40 exabytes of data, I found that Doctor Who is roughly 850 gigabytes, I found this on Reddit, very scientific. And the number is then 40 exabytes over 850 gigabytes, that's roughly 47 million copies of all the decades of Doctor Who media is what's necessary to reach the amount of data we expect from genomic research within a couple of years. So we need a technology capable of analysing the equivalent of 47 million copies of the entirety of Doctor Who, and currently, as you've both mentioned, AI provides the best way we have to do this.
Natalie Banner: Wow! So we are talking absolutely vast amounts of data. And I do love the analogies there, it's very helpful to actually sort of bring it home and make it real. So we're talking vast amounts of data and currently it feels as thought AI may be the best way to try to analyse and explore that scale of data. So given that's what we're talking about in genomics, in what ways is AI currently being applied in the field of healthcare and genomics? Francisco, I'm wondering, can you give us any examples of how Genomics England is integrating AI models and tools into its research efforts? And I know particularly we have a programme of work exploring multimodal data, can you tell us a little bit about that?
Francisco Azuaje: Absolutely. But first of all, just to give you an overview of the type of applications in research and healthcare, right now AI offers opportunities to develop tools that are needed to support interpretation of genomic variants, and the relationship between those variants and medical conditions, drug responses. AI is also a powerful approach to supporting the detection of diseases and some subtypes of these conditions, and matching those conditions to treatments, using different types of data, in the clinic this is happening already in the clinic, and examples of data include medical images, clinical report, electronic health records. So AI is already driving the development of personalised medicine for both research and healthcare purposes.
Now, at Genomics England we are investigating the use of AI to support a number of tasks with potential impact in both research and healthcare. In the context of healthcare, we are talking about AI tools that can support the prioritisation, the ranking of genomic variants to allow clinicians to make more accurate and faster diagnosis. You mentioned the multimodal programme at Genomics England, as part of our mission to enabling research, we are developing tools and applications to help researchers extract information from different modalities of data or data types. In this context, AI plays a crucial role to deal not only with the size and the volumes of this data, but also to allow the meaningful extraction of useful information with clinical value based on the combination of different data sets. And that's a complex challenge, that only AI can approach. Here, we're talking about large, diverse, and complex data sets coming from different types of clinical imaging modalities. We are talking of course about genomic data, clinical reports, and in general any information that is included in the patient's medical health record.
Natalie Banner: Thanks, Francisco. And can you talk a little more about the specific tools or projects you're working on at the moment in multimodal?
Francisco Azuaje: Absolutely. So, in the case of multimodality, we are talking about applications that aim to improve the way we connect any of these data sources, including imaging and genomics, with clinical outcomes. For example, how to improve the way we predict not only a diagnostic type, but also how that information can be correlated with the potential response of a patient to a particular therapy. Or a prediction of the potential evolution of that patient within a particular subtype of condition or phenotype. To do this we rely on a type of a machine learning technique called deep learning, just very briefly, deep learning models are again a branch of AI, so within machine learning, these models are very powerful tools that apply deep neural networks. These networks consist of multiple layers of mathematical transformations that are applied to the data. And these transformations allow them the automatic discovery of complex patterns in this data, including all these modalities that I mentioned before. So this is a key approach that we need to extract useful features with diagnostic or prognostic value from these different modalities of clinical information.
Natalie Banner: So there's obviously a really clear focus there on the benefits to patient, the patient outcomes, really trying to ensure that we can create personalised medicine as far as possible. That every patient can have an outcome that's kind of very much about their own particular circumstances and condition. So not just looking at individual patients, but broader, what does this mean for society? Ismael, I wonder if you can tell us a little bit, your thoughts on the questions about societal impacts with the increasing use of AI, particularly in genomics and healthcare more widely?
Ismael Kherroubi GarcĂa: Yeah. So my somewhat hot take is that AI only accelerates societal impacts that genomics research and healthcare can have. So the impacts, of course, will be diverse and complex and quite widespread, especially given the quite nuanced and sometimes difficult to understand areas of genomics and artificial intelligence. But the key takeaway from what I want to say is that, it only accelerates the impacts of genomics and healthcare. So if we take genomics research to promote human flourishing, ideally artificial intelligence will also only help further human flourishing. Conversely, applying artificial intelligence tools to genomics research can help perpetuate certain stereotypes and related harms. Genomics England has diverse data initiative and they show that Europeans represent 78% of people in genome-wide association studies.
The challenge here is that, if we train artificial intelligence tools on complex interrelations of mainly the genomes of people with European ancestry, then we are over-sampling people with European ancestry, and the findings will have very limited effectiveness on different populations, both around the UK and diverse populations around the world and within the UK. So whilst artificial intelligence will have societal impacts as a general sort of technology that can be applied to many different fields, in the context of genomics and healthcare, I think that the societal impacts we should really be focusing on relate with genomics and healthcare in particular.
Francisco Azuaje: I agree with Ismael, that the real value of AI is not only in the acceleration of technological progress, but in the impact at different levels of society. Including the way we improve health in an ethical way, and also in the way we support people to develop tools that have an impact in the way we operate as societies and the way we relate to each other. So I totally agree, it's more than just technological acceleration.
Natalie Banner: Absolutely, okay. So we've talked about the potential societal impacts, and I mentioned at the outset that there's a lot of hype and a lot of interesting narratives about AI in the public domain. Things can feel very utopian or dystopian as an awful lot of marketing, but understandably as well a lot of fear coming from the public perspective, especially if you think that most people's understandings of terms like AI have come from science fiction, for example. So, Ismael, what concerns are there from a public perspective? Particularly for, you know, when patients faced with the increasing use of AI and machine learning in genomics and healthcare, and the idea that their care or their treatment could be informed by these tools and technologies. What kind of challenges might arise for patients in the future as these technologies continue to advance? And what are the perceptions like from that public and patient perspective?
Ismael Kherroubi GarcĂa: I think you got it entirely right. The biggest concern relates with the public perception of AI and that perception in turn is significantly impacted by what we see in mainstream media, be it in the news media, social media in adverts, and so on. And unfortunately, as artificial intelligence is usually depicted as this extremely technical field, the conversation, the narrative is more often than not steered by big tech, so organisations and people with very clear agendas. The example I want to make this case with is this open letter, I think it was in March this year, which was put together by a series of company CEOs, a few researchers as well, and it's ultimately been signed by over 30,000 people. And this open letter called for a six-month pause on what they called 'giant AI experiments'. So this was an open letter and direct response to the launch of ChatGPT, which is an AI-based chatbot launched by Open AI in November 2022.
The open letter suggests that we might, in quotes, that 'we might be developing non-human minds that might eventually out-number and out-smart us. And we're risking loss of control of our civilisation'. These are extremely serious fears, and I would be really afraid if I believed them. So the concern here is that the fears aren't really grounded in reality, but in common fiction or narratives about AI. And very quick way to see that there's a lot of fiction around AI, if you go online, go to your favourite images browser, and look for 'artificial intelligence', you're going to find a lot of images of blue, floating brains, a few versions of the terminator, robot shaking hands with people.
There's one great image of a robot using a laptop â which always makes me laugh. These are not informative depictions of artificial intelligence, let alone genomics. And the risk is ultimately that, if the general public has easy access to unhelpful fictions about AI, then there's a great possibility that genomics research, which is going to remain intricately linked with AI advancements, will be perceived negatively, so genomics services fuelled by AI will not be trusted. And ultimately, given my stance, and I think the shared stance that AI is necessary for genomics, who's going to pay? Well, that will be the patient.
Natalie Banner: So we have quite a battle on our hands, in terms of trying to create space for those informative discussions, as you call them, Ismael, about the realities of what AI can and will be doing in genomics. Francisco, how are we addressing those kind of questions and concerns in our work at Genomics England? What steps do you think we can take at Genomics England to talk more openly about the work that we're doing involving AI to try and create space for those informative discussions that aren't led by the hype or the fears of AI?
Francisco Azuaje: I agree that we have to ensure that we are not distracted from many discussions that emphasise potentially fictional or existential risk of AI. I think there are valid concerns about existential risks that don't represent the AI fictional view of Hollywood, but that really affect the way we operate our societies. For example, existential risk for democracies, if you have monopolies of this technology. If we have less accountability, in terms of governance. If we have electoral systems that do not work. So if that doesn't work it's going to be very hard to benefit from AI within healthcare, so that's something to be considered as well. But I agree that sometimes the discussion is driven by this interest in very long-term potential scenarios. I think the key is to achieve a balance between longer-term and near-term priorities. And in the case of healthcare, there are many challenges and issues that we should be discussing and addressing by now, including challenges regarding the privacy and the respect of rights of our patients and individuals. Concerns about the biases embedded in the data used to build the systems, biases actually embedded in the practices for building the systems. So these are real risks, that in the case of healthcare and research need to be addressed now.
In the case of Genomics England, we are doing a lot of work that is laying the groundwork for safer, ethical uses of AI. So this means, for example, that we will continue doing what we do, inspire and driven by the need to respect our patients' our participants' privacy and rights and voices, so that's essential. In practice, this means that we work closely with our Participant Panel and different committees responsible and accountable for protecting these views and rights. From a machine learning point of view, there are technologies and tools that are quickly emerging that we are using to ensure that our systems are properly designed with ethical considerations in mind.
For example, we ensure that our data sets are of good quality, and good quality means not only the information that we want to use for a particular application, but also means that we identify and quickly mitigate potential biases embedded in the data. It also means that if we share a tool, for example, within our Research Environment, these tools have been properly tested. Not only for reliability but also for potential risks associated with privacy, with biases, etc., before these tools are deployed to a production environment or shared with the wider community. So these are basic steps, but I think they are essential, starting with the protection of our data and also by applying best practice in the way we build and evaluate these models carefully before they are deployed to a wider use.
Ismael Kherroubi GarcĂa: And that, to me, makes perfect sense, and it's always encouraging to hear the practices around AI and Genomics England. There is one challenge that came to mind that you mentioned, the impact of democratic values, on potentially artificial intelligence informing social media, that informs electoral processes. And there's another very real, tangible issue with artificial intelligence, which is the environmental impact. So what's really interesting, the challenge here is that artificial intelligence tools have significant environmental impacts. You have enormous data centres that need to be submerged in water, maintained, kept cool, and we're developing enormous algorithms, ChatGPT, and so on, that require these huge amounts of data I mentioned earlier on. So there is this really tricky balance between health and the natural environment, which I don't have the capacity to even begin to think about.
So, I sit on the Participant Panel at Genomics England, and the conversation often goes around how Genomics England use our data, how our privacy is preserved. But at the intersection of artificial intelligence in Genomics England, I might have slightly different concerns that don't relate directly with privacy. I usually think about three â scalability, automation bias and explainability. So I mentioned before that there's a risk of promoting issues that genomics research already faces, that over-sampling of certain populations. So if we take what genomics can teach us based on mostly European ancestry data, we end up imposing assumptions on populations across the globe. The role of AI here is in scaling the impact of those assumptions, taking bias algorithmic models, and applying them to diverse communities within and beyond the UK, risks not identifying certain conditions, missing patterns, potentially informing poor medical practices, if we take these bias data samples and ultimately algorithms. So the issue here about scalability is that artificial intelligence promotes the limitations of genomics research.
The second issues I mentioned on automation bias is about individuals, people potentially valuing the output of computational systems because they're mathematical and therefore might seem objective. And the challenge here is very real, if we have a clinician who is diagnosing someone and the clinician says no, there's no clear evidence for there being cancer. Following all the metrics that this clinician has learnt over the years of their work, and they're faced with an AI tool that says that this agrees that says actually there is a case for there being cancer or whatever the other option is. So the automation bias there, if it were to kick in, would be for the clinician to raise their hands, give up and say, "Well, the machine says that there is..." or "there isn't cancer, so we'll just go with what it says." The other option of is for the clinician to actually challenge what the AI tool says. And the crucial difference here is that the rationale of the clinician can be described, it can be outlined, explained. And that's the third issue, that's the issue of explainability.
So modern AI tools tend to use an enormous data set and neural networks or other machine learning technologies where outputs are produced with little or no explanation. The clinician can explain why they decided on one diagnosis or another, the AI tool cannot. Ideally, this is the really tricky bit, hospitals, Genomics England and others, would have the government structures in place to handle these discrepancies in outputs from clinicians who can explain what they have to say, and AI tools which are mathematically very sophisticated, they sound pretty cool, it's a challenge.
Natalie Banner: It absolutely is a challenge, and very helpful to talk through some of those broader ethical issues and questions. Because they are, they're questions to what I understand, you know, the law and regulation hasn't caught up yet with these very, very rapidly advancing tools and technologies. And actually, if we are working at the frontier of some of these, then these ethical questions are precisely the ones that we need to work how to navigate through. Not necessarily because of a regulatory structure, but just through bringing different voices, different perspectives to the table, trying to anticipate consequences, and thinking through where some of those questions, for example, as you raised on explainability, what could we do? Where could we address some of those challenges?
Francisco Azuaje: Yes. The issue of transparency is crucial, not only to ensure that we have useful tools, but to ensure that we improve privacy, that we respect the uses of these technologies. At the same time regardless of the techniques that we use to make systems more explainable or interpretable, the idea behind transparency also means, let's ensure that if we say that something works well, indeed, we are providing evidence that that something is working well. That means that we ensure that first of all we have reliable and robust systems, and that by doing that we are also bringing actual benefits to patients and society. So I think that's a more fundamental question than discussing which techniques can make this model or that model more explainable, or the actual practices for making something more transparent. So in general this transparency is there because we want to ensure that we deploy ethical, robust and fair systems. And that this starts by enhancing the quality and transparency of the development of the tool, but also the evaluation of those tools before their deployment, and even after these systems have been deployed to a research environment or to a clinical setting.
Ismael Kherroubi GarcĂa: It sounds like there's a need for continuous monitoring, right. Throughout the life cycle of developing an AI tool, but also once implemented how we get feedback, so that the tool can be improved, but also future and other tools can be improved.
Natalie Banner: Thank you so much. So we have had a real whistle stop tour through the world of AI and genomics. We've highlighted some real potential advances in exciting areas. We've cautioned about some of the risks and questions about how to tackle some of the ethical complexities that are emerging. So just to wrap us up, Francisco, can I turn to you first, could you tell us what you see as being the biggest or the most significant impacts in the world of AI and genomics in the next, say, three to give years?
Francisco Azuaje: In the next three to five years, we should expect significant advances in genomics, AI genomics, beyond the focus individual genes or markers or actually the idea of gene panels. So we should expect that the full patient genomic analysis will become more common to provide a more comprehensive view of genetic influences on health, and also the combination of genomic data with other types of health information will offer deeper insights for supporting more accurate, faster medical decision-making.
The challenge lies in connecting this data to clinical decisions moving beyond diagnosis to actually recommend personalised treatment options. Matching patients with relevant clinical trials based on their genomic and other types of clinical information will also become more effective, more efficient. However, concerns about reliability, safety of these applications remain, and I think that in the next few years we will see an acceleration in the development of tools and applications. But also an improvement in the way we evaluate these tools before they are deployed to a real-world environment. So this will be crucial in the next few years, and despite all these challenges, there is reason to be very optimistic about the future of AI in genomics and medicine for the benefit of patients.
Natalie Banner: Thank you, Francisco. And Ismael, a last word to you, what's your key takeaway for those developing AI tools for use in genomics?
Ismael Kherroubi GarcĂa: For me the biggest challenge is that there must be multidisciplinary approaches, so those developing these tools need to speak with one another and be exposed to patients. So, on the one hand, AI tools for medical applications must involve multidisciplinary collaborations, critically including the voices of clinicians, and that point was raised by Francisco. And the COVID-19 pandemic, to work with something... work for an example, already showed us the value of behavioural and other social sciences in understanding the impacts of public health policies. So genomics and general genomics research must consider multidisciplinarity in a similar way and bring different disciplines together.
On the other hand, genomics data remain intricately linked with individuals. Research participants and patients must be kept abreast of developments in the complex space that is this interaction of AI and genomics to avoid the trust issues mentioned earlier on. Ultimately, those developing AI tools for use in genomics must follow inclusive practices.
Natalie Banner: We'll wrap up there. Thank you to our guests, Ismael Kherroubi GarcĂa and Francisco Azuaje for joining me today as we discussed the role of AI in genomics and healthcare, and the importance of having open, informative conversations about both the promises and the challenges in this exciting space. If you'd like to her more like this, please subscribe to the G Word on your favourite podcast app. Thank you for listening, I've been your host, Natalie Banner.
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In this instalment of The G Word, our guests engage in a compelling discussion centred around a recently published paper that supports the integration of whole genome sequencing into standard cancer care.
Our guests shed light on the transformative potential of combining health data with whole genome data. Discover how this innovative approach empowers doctors to deliver more personalised and effective care. Our guests delve into the findings of a landmark national study, unravelling the significance of identifying inherited cancers for patients and their families. The episode explores not only the scientific advancements but also the real-world impact on individuals facing a cancer diagnosis.
Our host Naimah Callachand is joined by Dr Nirupa Murugaesu, a Consultant in medical oncology at Guy's and St Thomas' NHS Foundation Trust, and the Principal Clinician for Cancer Genomics and Clinical Studies at Genomics England. And by Professor Sir Mark Caulfield, a Professor of Clinical Pharmacology at Queen Mary University of London, and who previously served as Chief Scientist for Genomics England and was instrumental in the delivery of the 100,000 Genomes Project.
"In cancer we were sequencing sections of the tumour and comparing them to DNA inherited from your mum and dad, and that comparison allows us to work out what is driving the cancer, what may be affecting its potential for treatment and how we might choose treatments for patients. So this is a real opportunity to create precision cancer care."
You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/Whole-genome-sequencing-in-cancer-care.docx
Naimah: Welcome to the G Word. What does it mean if we can test for inherited genes?
Nirupa: It can influence how their cancer is treated. So it means that there may be certain types of therapy that are available if they have a specific inherited cancer gene, number one. It also can impact in terms of preventing further or other cancers related to those genes, and it may impact the type of surgery they have, and also the type of overall cancer treatment. And then finally, if they have got an inherited cancer, then, as I mentioned before, it may impact in terms of testing and screening for their family members.
Naimah: I'm your host Naimah: Callachand. Today, I'm delighted to be joined by Dr Nirupa Murugaesu, who's a consultant in medical oncology at Guy's and St Thomas' NHS Foundation Trust, and the principal clinician for cancer genomics and clinical studies here at Genomics England. And Professor Sir Mark Caufield, who's a Professor of Clinical Pharmacology at Queen Mary University of London, and who previously served as chief scientist for Genomics England and was instrumental in the delivery of the 100,000 genomes project. Today, Mark and Nirupa are going to discuss key findings from a recent paper that's just been published in Nature. If you enjoy today's podcast, we'd really love your support. Please like, share and rate us on wherever you listen to your podcasts. Now, let's get into the interview. So first of all, Mark, I wondered if you could give me a bit of background on the 100,000 genomes project?
Mark: So the 100,000 genomes project started in July 2013 following an announcement by the then prime minister, David Cameron, that the UK would be the first health system in the world to sequence 100,000 whole genomes, which is as much as you and I can read of the genetic code. In the case of cancer, which we focused on here, in cancer we were sequencing sections of the tumour and comparing them to DNA inherited from your mum and dad, and that comparison allows us to work out what is driving the cancer, what may be affecting its potential for treatment and how we might choose treatments for patients. So this is a real opportunity to create precision cancer care.
Naimah: And Nirupa, can you tell me what the 100,000 genomes project meant for these patients with cancer?
Nirupa: I think, firstly, we're very grateful for all of the participants in the programme, because what it's allowed us to do is to look at the data as a whole, and having all of that sequencing data alongside clinical information has been incredibly valuable, it has also developed the infrastructure for testing. And really I think for patients with cancer, they participated in this programme as a research project, and unusually for a research project these results were returned back to treating clinicians to clinical teams, if there may have been a result that would impact or change their management. But I think, importantly, what it enabled is the implementation of standardised cancer testing in the NHS, and really enabling that for a wider range of patients, not just those that participated in the project. And because of patients participating, this then allowed all of the data to be stored in a single place, and this has been incredibly valuable for clinical academics and researchers.
Naimah: And can I ask what specific types of cancer that were looked at in 100,000 genomes project?
Nirupa: Again, the project was set up such that we allowed a number of different types of cancers to be sequenced and, therefore, very permissible, because we also wanted to ensure that some of the less common and rarer cancers were also sequenced and, as you would expect, more of the common cancers as well. In addition, I think the opportunity to sequence paediatric cancers, as well as haematological malignancies, or blood cancers, was also key as part of the cancer programme. Here, we focus on the solid cancers, but obviously there was a much wider range of cancers that were sequenced.
Naimah: And next, can we move on to talk about the findings of the study?
Nirupa: I think, firstly, by undertaking sort of a pan-cancer analysis, it really gave us an overview of the number of target and genes that were found to be actionable. And what I mean by that is that they have a, well, clinically relevant, and we can see that in certain cancer types, such as in brain cancers, in colon cancers, lung cancers, there were within the genome sequence more than 50% of these cancers had something that was what we would call actionable. So there was a mutation in a gene for which this would influence treatment. And as we started to look more across the entire cohort of patients, you can really get an idea of the fact that the more that we sequence, and the more comprehensive the testing is, the number of different types of mutations that we were able to discover.
Naimah: And when you mentioned that these findings were actionable, what does that mean?
Nirupa: So what that means is that has an impact in how the patient will be managed and treated. It may influence, firstly, the type of surgery they have, it may influence the type of cancer treatment that they receive. And all of this, I suppose, comes back to the point that Mark mentioned, of precision oncology, so we more precisely treat patients based on their individual cancers.
Naimah: And could you give me some examples of maybe some of these genes that were found in the study that were actionable?
Nirupa: Yes, so the types of genes also matter, or the type of mutations. So some of them were in known cancer genes, and if you have, for example, a mutation in lung cancer, in a gene called the EGFR gene, we know that there are cancer therapies that can be provided that target specifically this mutation. So that's one example, and this is quite well characterised and understood in oncology care. But what we were also able to do with whole genome sequencing, is identify different types of mutations that are harder to characterise routinely. And these are often included things that we call pan-genomic markers, where we can see what the mutational landscape is of the cancer, the different patterns of mutations can be gleaned from this, and often this can then give you an idea of the underlying biology of the cancer. But importantly, in certain types of cancers, such as high grade serious ovarian cancer, it highlights which patients may have a particular marker that means they may or may not benefit from a particular type of therapy. So in this particular case, the class of therapy is called PARP inhibitors.
Naimah: And how did the study compare to other similar stuff studies in the genomics area?
Nirupa: That's a really good question, and I think we looked at this from other large sequencing endeavours, such as the ICGC, TCGA, so these are big studies where have been whole genomes sequencing. Also within the Hartwig Institute in the Netherlands, they've also undertaken whole genome sequencing for cancer patients. And what we were able to identify is that the patterns of mutations were as expected, we found, you know, a lot of similarities. I think the difference, the main difference is not just identifying the type of mutations across the different cancers. But the fact that we were then able to look at the longitudinal outcome, and correlate some of these genomic markers with outcomes related to both therapies, as well as survival impact of having certain mutations in terms of prognosis.
Naimah: Mark, do you have something you'd like to add there as well?
Mark: Yeah. So one of the things that we did in the 100,000 genomes project, was to evaluate the best way of measuring the whole of your or my genetic code. And we discovered that very early on that if you expose the tumour to a preservative, which is called formalin which keeps the tumour preserved, that actually you could get quite a number of misleading findings. And so to address that, the distinctiveness from former programmes, such as Nirupa mentioned, like the Cancer Genome Atlas, is that all of the tumours that we studied in this paper were actually produced under fresh tissue conditions, and have not been exposed to a preservative. And that means that what we have is a really accurate reflection of the variation within the tumours. And the other thing about this particular resource is it's the biggest resource. We were able to look at 13,000 people with solid tumours, but we also had blood cancers and other cancers which also feature of this paper.
And a further remarkable thing about this is early on, Nirupa and the team and I decided that we would longitudinally life-course follow the patients and by accruing data from multiple sources in the health system. So, every attendance at the hospital, what chemotherapy was had, we've been able in this paper to recapitulate signatures that clearly show that certain mutations are harmful. And many of the findings that we've made are absolutely, if you look at the survival of patients particularly, you can see almost identical patterns to those in clinical trials. What this means is that by the really rich data set which is now many billions of clinical data points on these patients, we can actually look for long-term signals of benefit and harm that perhaps would not be detected by a clinical trial that might last for six months or a year. So this is a really valuable resource, and the really great thing is we can use what's called real-world data, which is where we take routine health data, and we can recapitulate the findings from tightly controlled clinical trials. And I think that's quite an important finding.
Naimah: That kind of brings me onto the next question, Mark, where I want to talk about the value and benefit of genomics sequencing for cancer patients. I wondered if you could expand?
Mark: Well, what we know from one of the genomics medicine centres which were regional hubs, is that they use the information that we return, that Nirupa outlined earlier in a report, for 25% of their patients. Which means that they concluded having evaluated that as the clinical team locally, that there was something the patients could benefit from. Now, what we think is this makes the case for certain cancers being part of the national genomics test directory whole genome sequencing, but it's still the case that the majority of testing for cancer is now very large focused panels that are focused on specific gene features. But in some measure, this work is also able to reassure us that those gene features are the right ones to focus on, so this work has been very useful in that respect, even where the NHS today cannot make the financial or clinical case for using whole genomes in specific cancers. So I think the programme's made a massive difference.
The biggest thing it's done for patients, which Nirupa was very actively involved in, is it's allowed us to create a national genomics test directory. So when we started this, cancer genomic testing was completely random and would vary from one postcode to another, one hospital to another. And what Nirupa and the cancer team created is a national cancer genomic test directory, which now means that standard of care, that's the basis for reimbursement, and it's available across the landscape of 56 million people. And given that one in two of us will have cancer, this is a massive advance.
Naimah: Yeah, you've really highlighted the impact of having access to such a large database. And I just wanted to ask as well, what are the challenges associated with implementing routine whole genome sequencing into clinical care?
Nirupa: I think as with all of these things when implementing something new within a healthcare system, it requires a level of education, upskilling and also, as Mark has touched on, how we handle the tumour tissue, so that it's handled in a genomic-friendly way to enable the best results if you like, because we want to ensure that their DNA is not damaged so that we can get accurate read-outs on the results. So there are challenges and there is also cost implications in weighing up the pros and cons. And I think what we were able to show, and by undertaking this sort of pan-cancer analysis, is where there are those cancer type where there is a real need for whole genome sequencing, or where it can be justified, because there are a number of different types of mutations both within the tumour. And also from a blood sample that is also taken, so this is your constitutional DNA, so this is if there is a risk of an inherited cancer. So we are able to pull together all of this information, and obviously that's important, not just for the patient, and their management, but also for family members. So I think really what this shows is that where you have to identify many of these different types of mutations, whole genome sequencing enables that through a single test.
Naimah: Mark, would you like to add something else there?
Mark: One thing I think which Nirupa's very much part of, is the distinctiveness of the Genomics England approach has been to involve the NHS at every stage. Now, what that means is we estimate that at the peak of the 100,000 genomes project, 5,000 frontline NHS staff touched the project at some point in their working week. What that does mean is that Nirupa and the cancer team could realign the cancer tissue handling pathways. But it also meant that we were able to upskill the frontline workforce, such that at the end of the programme, when we produced a genomic test directory, they were really up for it because they did not want all the hard work they'd put in to stop. And so what we've done is produce the national test directory within five years of starting, that wasn't a deliverable for the project, but it was nonetheless obvious to all of us working in it, including NHS England, that there needed to be service transformation, and we've managed to effect it.
Now, if you look at other settings where perhaps Nirupa and I might have a research team, we might do it some distance from the health system, it would be in the health system, but not with the health system, then it takes between nine and 16 years to get these things into clinical practice. And that was achieved here in five years. So there is a lesson from this, the cancer programme particularly, because the cancer programme testing was very limited when we started, but you can take an entire workforce on a journey and leave them with the legacy of an entirely transformed system for patients. And thankfully because we got, Nirupa and I, the NHS to agree to reimburse for the testing directory being used, we have eliminated a lot of randomness that was in the system previously. So it's quite an important advance in that respect, and it really does show in the beautiful work that Nirupa was describing exactly how you can use this information to change an entire system. And the NHS is not the easiest system to change in the world.
Naimah: Nirupa, you mentioned the findings show that there was potentially inherited genes. Can you tell me what does that really mean for patients, if we're able to diagnose these inherited genes sooner in life?
Nirupa: It can influence how their cancer is treated, so it means that there may be certain types of therapy that are available if they have a specific inherited cancer gene, number one. It also, can impact in terms of preventing further or other cancers related to those genes, and it may impact the type of surgery they have, and also the type of overall cancer treatment. And then, finally, if they have got an inherited cancer, then, as I mentioned before, it may impact in terms of testing and screening for their family members. And that's really key as well, because this means that their cancer can be diagnosed, if they do develop a cancer, because they're being monitored, because it's much more targeted, their approach in terms of screening for a particular type of cancer, they can potentially have their cancer treated much earlier. Or even better, before it becomes what we call an invasive cancer but at the pre-cancerous stage. So this has huge implications, and what we're finding actually with more and more testing â and this is not just... our study was consistent with other studies that have been published â is that when you undertake more routine testing, then you are able to identify this. It is not common amongst the population, but in those patients where it is relevant, it really can impact their care.
Naimah: Mark, do you have something to add there?
Mark: Well, I think Nirupa's just highlighted a really important point. So to bring that into a little bit more ways of which people listening to this can relate to it, we have a family where there was a women who had no family history of breast cancer, she developed breast cancer, and in the tumour we found that she had a BRCA 2 mutation. We also found that she'd probably acquired that or inherited it, we don't know. That for her meant that she could enter the Olympia trial, which was running at the time, which Nirupa alluded to earlier, was a study of PARP inhibitors. But without that genetic makeup she'd never have got into that trial, and she probably wouldn't have been tested for BRCA at that time in the NHS because she had no family history, I think that's probably right, Nirupa.
And then there was a family-wide consequence for that, because she had a brother and son, and she also had a daughter, and the daughter was under 30 at the time and underwent BRCA testing and was BRCA 2 positive. But she has the opportunity now to enter intensive breast screening from the age of 30, and that's what's happened. And her brother, and this is the lady who had the breast cancer, her brother and her son may be at risk of prostate cancer, so they can consider testing. So Nirupa makes a really important point, that when people have inherited a previous disposition to cancer, that can have a family-wide impact. And one test in one family member can open the doors to opportunity for others to understand their risk and to be screened more actively and intensively, hopefully with meaning that if they do develop cancer it will be detected very early, or maybe we can just prevent it altogether.
Naimah: Thanks, Mark, a really good example of the impact that this testing has had. I just wanted to touch back on your point, Mark, that you'd made about real-world data. And I wondered actually, Nirupa, if you could kind of explain to me why it's important to link real-world data to the genomic data?
Nirupa: Yeah. So I think the work we've done here really does emphasise this, because when we refer to real-world data, we're talking about different types of healthcare data across the population. And we had the opportunity to link the genomic data to a number of key data sets that are curated by the cancer registry, the national cancer registry database. And this includes things like all of the population base systemic anti-cancer therapy, so we know that for each of the participants the type of cancer therapy they receive, and also, as Mark has mentioned previously, the hospital episode. So when patients needed to be... we can see their data in terms of admissions, investigations, and so on. And these are really valuable data points, because you get an indication of when patients may have had to then have further testing, or if there is a risk of recurrence and importantly survival data, because a lot of this has been, in terms of a lot of the cancer genes have been well characterised and tested.
But what we were able to do here at a pan-cancer level on a large cohort of patients over a period of time, is to look at if you had a particular mutation, what is the impact of that in terms of outcome for a particular cancer type, and even more broadly, on a pan-cancer level? And actually, as this type of data accumulates, I think the real value, and if you've got a larger number, you know, what is the value for patients who've participated in this programme going forwards, is that as that data accumulates and the numbers go up, we are able to then ask more detailed questions. What is the impact of a particular type of mutation, or a particular type of variant within a gene? And, importantly, what happens when you get a different sequence or a combination of genes? And how does that impact? And this, I feel, is the way that we are going to move more towards precision oncology, because we are beginning to understand the cancer in more detail, how it is going to behave, and then try and tailor therapies accordingly.
Naimah: And Nirupa, I wondered if you could tell me as well if the findings from this study have benefited directly those patients that were involved in the 100,000 genome project?
Nirupa: It has benefited some of the patients because, as Mark has mentioned, there are findings that we weren't expecting in terms of potentially inherited cancers and, therefore, this has had implications. The way that the project was set up from the outset, is that we were obtaining tumour samples from patients who had not received any previous cancer therapy. And what this meant is that this was predominantly in patients, so they were treatment naĂŻve with early stage disease that were having surgery to treat their cancers. And as such, what we know is that fortunately most of those patients did not require further therapy, because their cancers were treated successfully with surgery. But what it did tell us, and what it's really highlighted, is the number of important genes that were identified. And so whilst it may not have impacted patients directly, it's enabled us to study the biology of the different types of cancers, how they behave, along with the longitudinal clinical data.
But what it is doing now, is through the national test directory through the genomic medicine service, is enabling testing for patients that unfortunately now have more advanced cancers, but where these genomic findings are more likely to impact directly in terms of therapy. So, for instance, as we've mentioned, the ability to have whole genome sequencing for patients with high grade serious ovarian cancers, means that this will impact the type of treatment they have. And this also was the tumour type where we found the highest number of patients with BRCA mutations, so we have a potential inherited risk of a cancer as well. So now what we have learnt and the infrastructure that we have developed has enabled this to have a real impact, not just for patients in the project now, but wider within the NHS.
Naimah: Mark, would you like to add something else there?
Mark: I think Nirupa's encapsulated it very well. There were a range of benefits, so I mentioned earlier that in one centre 25% we have evidence got a benefit for their treatment for their cancer in some way shape or form. So an example to what there might be is that some people got a medicine they wouldn't have received from routine care, and that might have been licensed for the treatment of that tumour, but it wouldn't have been the first line treatment choice. Some people got medicines that they wouldn't have got because we don't normally associate using that medicine with that cancer, but they had a signature that showed that they were very likely to benefit. Quite high numbers got an opportunity to get into a clinical trial, which is really important because if you look, over 50% of global oncology trials now have some kind of biomarker or diagnostic, or something like this alongside, what better than to have a comprehensive inventory of the variants and the cancer, and to be able over time to use that library to understand better the treatment course of that patient. And that's what I think a whole genome adds, rather than the single, look at a single part of the genetic makeup.
And then finally, some had lots of mutations, really high rates of mutations, and maybe they should receive specific advance therapies, like immunotherapies. Or alternatively, they had a feature in their genetic makeup which it looks like they inherited, as Nirupa absolutely correctly said earlier, these people need to be followed-up and they need more intensive screening, because this is how you detect cancer at an earlier stage. And the final way people benefited is we could detect genetic changes in their DNA that meant that if they were exposed to certain medicines, they were likely to suffer harm. And there's a particular, two medicines, 5-fluorouracil capecitabine, where possibly about 5% of people will need either a reduced dose or a completely different medicine, because it will be very harmful. And so this is about getting the right medicine to the right patient first time, and getting the right outcome for that patient downstream.
And I think, you know, Nirupa's encapsulated it perfectly, there's a whole range of benefits that the patients can accrue from this. And I think we should probably, Nirupa, say that people were quite cynical when we started, about what it would be that you would get over and above, for example, the cancer genome map that's at the international cancer genome consortium. And, you know, I'd had leading cancer scientists in Britain say, "Oh well, we've discovered it all, there's nothing to find here." And I think what this paper shows is that's not entirely true.
Nirupa: I would agree with that Mark, but I would also probably add that it highlights the value of having a large data set alongside that clinical information. And what we were also able to do, is whilst we very much talked about what were the gene targets that had a direct impact or genomic markers that impact care now, for which there is an approved therapy. What we've also been able to do through this analysis, is actually highlight the number of mutations that have been identified for which there is a licence therapy in another cancer type, but not in that particular cancer type. And what that means, is that specially now, as we have more and more biomarker-driven therapies, I mean, if we look at that compared to when the project started and now, that has increased dramatically. And what that means is then there are sort of licensed medications that actually can be used in non-licensed indications via a clinical trial, via these very, you know, these basket studies which are across cancer types and are actually based on different types of molecular markers. And really, we're able to show this at a pan-cancer level across the 13,000 tumours through the results from whole genome sequencing.
Naimah: You've both kind of touched on this throughout and, you know, we've talked about the development of personalised medicine. And where do you see the future of cancer treatment in the next five years? Maybe, Nirupa, we can go to you first?
Nirupa: That's a very good question. I think and what I hope is that with more comprehensive and equitable and standardised testing for patients, especially within the NHS, that this will enable more personalised and targeted therapy alongside, you know, systemic chemotherapy. And as well as that, better selection of patients that are likely to benefit from the newer immunotherapies. And also where sequencing is very exciting, is that once we begin to understand more about the individual tumours, you know, going forwards there are a number of cancer vaccine trials, and the aim of those are to have specific vaccines that are going to target an individual's tumour. So I think in the next five years, this is I think a very exciting space, I hope so, because we need to keep doing more in the space for our patients to try and improve therapy and precision oncology for them.
Naimah: And Mark, do you have anything to add to that point?
Mark: I think Nirupa's right, that there are new therapy extractions coming on, vaccination's one way. But I think that what will become clear is whether we can use any molecular mechanisms for early detection of cancer. The battleground here is that we all too often detect cancer late, when it's already outside of the organ it originated in and may be spread in other parts of the body. It's very hard to effect a cure, almost impossible in that setting. But what if we could detect cancer earlier? And then what if we could place a whole genome or detailed molecular characterisation alongside that? And then, as Nirupa suggested, give someone a vaccine tailored to their tumour that would eliminate it. The real problem is all too often we detect cancer late, so maybe some of these new molecular diagnostics, such as cell-free tumour DNA will usher in an era of early detection.
And one of the things, and particularly before we did this project but also up until the beginning of the last decade, there were very few good biomarkers of cancer that were usable in the health system. So we have for the first time opened the vista of having early detection, if we combine early detection with detailed molecular characterisation, possibly a whole genome, possibly another test, then I think we really can usher in the era of precision medicine. And so I think Nirupa's absolutely right, there will be new treatments, there always will be, but what we have to do is to get detection at an earlier stage.
Naimah: We'll wrap up there. Thank you to our guests, Dr Nirupa Murugaesu and Professor Sir Mark Caulfield for joining me today. If you'd like to hear more about this, please subscribe to the G Word on your favourite podcast app. Thank you for listening.
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As we approach the conclusion of 2023, we reflect on a year that not only signifies our 10-year anniversary but also marks another chapter of The G Word. Throughout the year, guests have joined us fortnightly to share their research, stories, and aspirations for the future of genomic healthcare.
In this special end-of-year episode, Naimah Callachand sits down with Dr Rich Scott, Interim Chief Executive Officer at Genomics England, to look back on the last decade of Genomics England. Tune in as we revisit memorable moments from the 2023 podcast episodes through key quotes, reflecting on the transformative journey of Genomics England. Join us for this insightful recap and a glimpse into the exciting future ahead!
Below are the links to the podcasts mentioned in this episode, in order of appearance:
Adam Rutherford, Laurence Hurst, Cristina Fonseca and Vivienne Parry: Public views on genetics - what have we learnt? Dr Jack Bartram: Can genomics improve our understanding of childhood cancers? Helen Webb, Lizzie Mordey, Kirsty Russell and Prabs Arumugam: How can advances in genome sequencing support patients through their sarcoma journey?Vivienne Parry and David Bick: Which conditions will we look for initially in the Generation Study? Dr Nicola Byrne: What are the challenges of data governance in the digital age? Chris Wigley: The journey to the Human Genome Project and beyond with Dr Francis CollinsâWeâre also looking to the future where, as I say, weâre proud of the impact that there already has been, and the NHS Genomic Medicine Service is the first national healthcare system to offer whole genome sequencing and that is extraordinary. Thinking about how we can broaden our impact is a really important part of that, and thatâs thinking about how we can be supportive of genomic technologies broader than just whole genome.â
You can read the transcript below or download it here: Reflecting-on-2023-transcript.docx
Naimah: Welcome to the G Word.
Rich: Weâre in an extraordinary time. The power to analyse genomic data has changed enormously. These are big changes in terms of the, sort of, analytics that AI could bring and the potential to work not just within the UK but with other countries and other big initiatives to make sure that weâre answering the questions as best we can.
Naimah: Iâm your host Naimah Callachand and today weâll be hearing from Rich Scott, Interim CEO for Genomics England. Heâll be sharing insights with us from the last year, and weâll be revisiting key moments from earlier podcasts in the year featuring some of the voices that have shaped our discussions. If you enjoyed todayâs episode we would love your support, please like, share and rate us on wherever you listen to your podcasts. Now letâs get into the interview.
So, this year we celebrated our ten-year anniversary and as 2023 comes to a close we want to reflect on our achievements not just in the last year but over the last ten. So, Rich first of all can you talk us through where we started in 2013 and where we are now?
Rich: Itâs amazing really to think about how much things have changed in terms of genomics in clinic and in hospitals and then for us as Genomics England over the last ten years. So, actually thinking back ten years ago was only ten years after the Human Genome Project was completed, and when one thinks about what one could do in clinic and those questions you could answer using genomics in clinic. We could see what was coming, we could see these new technologies, next generation sequence in coming, but it was much more dependent on very targeted testing.
And now with, you know, our founding project, the 100,000 Genomes Project that Genomics England was founded to deliver in partnership with the NHS we asked the first big question if you like which was how can whole genome sequencing play a role in routine clinical care. And thatâs now played out where evidence from the project, what weâve learnt, the infrastructure weâve built, and also evidence from around the world that through the NHS Genomics Medicine Service has now put that into practice and weâre working in partnership to help them deliver it.
So, it has gone from an idea where we could see this new technology, this potential, to a position where now patients in the NHS with cancer or with rare conditions have whole genome sequencing as a routine part of their clinical care where thatâs in that national genomic test directory that NHS England have set up.
Naimah: Earlier in the year we heard from Dr Adam Rutherford, geneticist, author and broadcaster who commented on how the public perception of genetics and science has evolved over the last few decades.
âIâve been doing this a long time and I think that when it comes down to it, genetics which is a relatively young science and really in a sophisticated way, you know, a mere few decades old, but what is it at its absolute core, itâs thinking about families, itâs thinking about inheritance and itâs thinking about sex. And these have been the major preoccupations of humans for thousands of years, and itâs only really in the last century, really only in the last 30 years or so, that weâve had a sophisticated understanding of how these things work, if indeed we have had at all.â
Naimah: Letâs get back to Rich.
Rich, Iâve already touched briefly on it, but can we dive a bit deeper into the 100,000 Genomes Project and can you tell me a bit more about how it started.
Rich: Yes, so the 100,000 Genomes Project as I said was there to ask what role can whole genome sequencing play in understanding medical conditions, you know, is it ready for clinical prime time. And also how can we link routine clinical care to research so that weâre not just asking questions with todayâs knowledge, but we can continue to build that knowledge for the future.
So, the 100,000 Genomes Project was driven by that idea that people realising, the government realising and the NHS forming a partnership with us Genomics England to explore that question in real depth. And itâs not just about the clinical aspects and the scientific questions, it has also been working with participants and the public to understand how we could do that.
And through the 100,000 Genomes Project we worked particularly with patients with cancer and rare conditions to see how we could help make diagnosis and improve care. And also with their consent make their data available in our secure, trusted research environment so that researchers could continue to look for answers that we couldnât answer today, and we continue to do that work for those participants now.
Naimah: Next weâre going to hear from an interview with Dr Jack Bartram, a Consultant Paediatric Haematologist at Great Ormond Street Hospital for Children. He spoke about the significance and impact of integrating genomics into routine clinical care in diagnosing cancer in children.
âIf I look back and if I reflect on the last three years, you know, we could probably accurately say at least a quarter of patients it has given us additional information which is either aided in diagnosis or like I had said help risk stratify a patient or potentially reveal a target for a therapy that we didnât know of before. And what this has led to and what weâve seen over the last three years or so is that we have actually changed management of patients based on this.
So, definitely weâve got examples where we scan clarify the diagnosis, weâve changed the risk category, or weâve identified for example that an unexpected cancer predisposition in a family which has then led onto screening for the family which can then give the family the knowledge to try and do things to either modify the risk of cancer in the family or at least screen for it so they can detect things early to prevent things presenting too late.â
Naimah: Okay, now letâs talk a little bit about some of the initiatives at Genomics England. Can we talk about how theyâve progressed and what they might look like in the future.
Rich: Yeah, so we really are on a journey both as an organisation but with all of those partners that we work with across the UK system. And one of the great things I think about genomics and genomics in the UK is that the ecosystem that weâre in and the strong partnerships that we can form to ask these really big questions. So, if you like when we formed as an organisation we had the questions that weâre asking around diagnostic use of whole genome sequencing in the 100,000 Genomes Project.
And if you like in our second chapter as weâve moved on to support the NHS in delivery of life clinical care we also have been thinking about the other big questions that we need to address. And those have played out and weâve been really fortunate to gain the funding and to work in partnership with the NHS and others on these big questions. So, firstly our newborn genomes programme, secondly our diverse data programme and then our cancer 2.0 initiative.
And each of them have big questions behind them so that weâre saying, you know, where could genomics better support healthcare and move forward and improve care for everyone. Our vision at Genomics England is a world where everyone can benefit from genomic healthcare and each of them is pushing those boundaries, asking those questions in different ways.
For the newborns programme the big question is should every newborn baby be offered whole genome sequencing driven particularly by that potential to identify more treatable severe genetic conditions at birth, and if so how should we do that. Again, developing evidence in and around really broadly across the clinical and scientific aspects, but also engaging and understanding public attitudes how we might do that. And really understanding how that might impact on the healthcare system, how it might be delivered in clinical care.
For the diverse data initiative we recognise the challenges historically that there have been because of the inequity in terms of the communities who have been engaged with and included in genomic research. And the diverse data initiative aims to both understand where we are today but also to make sure for example the national genomic research library is at least representative of the UK population so that we can work towards again that word thatâs in our vision, everyone, a world where everyone can benefit from genomic healthcare.
And in the cancer 2.0 initiative weâve been exploring two really promising areas in terms of cancer genomics. Firstly, exploring different sequencing technologies and in this case partnering with the NHS to work on the Oxford Nanopore technology which we think is really promising in terms of use in diagnostics to speed up and better diagnose and treat cancers.
And also looking in our multimodal element of our cancer 2.0 initiative at bringing in a broader range of data alongside the genomic and clinical data that participants in our programme consent to us holding in our trusted research environments. And bringing in image data, images of their tumours on the histopathology slides that are looked at traditionally down a microscope but scanning those at very high resolution and with uniformity between participants working with NPIC to do that.
And also bringing in imaging, so radiology type imaging, of tumours so that that data is there to drive new discovery. And working in partnership with academics and with industry for example insitro to understand how we can both bring that data together usefully, put the right tools next to it and then allow that discovery so that our participants know that weâre looking not just on what we know today but to improve things for the future.
Naimah: Rich mentioned some of our initiatives here at Genomics England. And now weâre going to hear from some G Word guests on how these programmes can make a difference for those with a genetic diagnosis. We spoke to Lizzy Mordey, a clinical trials co-ordinator, whose husband Steve sadly passed away last year after receiving a sarcoma diagnosis. Lizzy commented on the pivotal role whole genome sequencing can play in receiving a quicker diagnosis on the identification of suitable treatments for patients with sarcoma.
âPersonally, I would hope for quicker diagnosis, and I know thatâs super hard to do and I think as weâve discussed before on this call itâs such a rare thing and it, kind of, often doesnât fit the standard clinical pathway and thatâs one of the reasons why itâs so frustrating. So, anything that we can do on that front that I think would be hugely valuable to anyone experiencing a journey like what me and Steve went through, and yes advances like genome sequencing are really amazing in supporting that. Yes, as I mentioned as well any information about types of treatment, you know, the diagnosis is important but then the other aspect of getting a diagnosis and a specific diagnosis is understanding whatâs most likely to help.â
Naimah: Next weâre going to hear from David Bick who is a principal clinician for the Newborn Genomes Programme at Genomics England. He spoke about the generation study which is being delivered in partnership with the NHS.
âIâm doing this because I imagine a day when all over the world we will find and treat children before they get ill. This is one of the most wonderful programmes to be involved with because I can see that future. I want there to be a healthcare system. I really want to help children stay healthy and really live their best lives, thatâs whatâs so exciting for me.â
Naimah: Now letâs get back to the interview with Rich. You mentioned all of the partnerships there and also one important one is with the NHS. As you know the NHS also celebrated its 75th anniversary year as well as our tenth anniversary. And I wondered if you could tell me a bit more about that relationship with Genomics England and the NHS and how weâre working together.
Rich: Our relationship with the NHS is absolutely critical. So, as weâre thinking about what we can do to enable better genomic healthcare weâre so fortunate in this country to have a national healthcare system. And for us and for our work at Genomics England itâs absolutely critical to work hand in hand with NHS England both in supporting their live clinical services so we enable their national whole genome sequencing service through the Genomic Medicine Service and also as we work through all of our patient facing research.
So, as we did for the 100,000 Genomes Project, as we are for our Newborn Genomes Programme and so forth co-designing these programmes so that the evidence that weâre able to generate is relevant in the UK for our healthcare system but also that national scale is just so extraordinarily powerful. And I think weâre really lucky for many reasons, the UK genomics ecosystem, itâs richness, the investment that has come from government and from the NHS in genomics and the recognition of its importance and from funders, and then that ability to ask questions at national scale.
And when you look internationally I think thatâs the piece that people are often most jealous of in terms of the power of the questions that we can ask together with the NHS so that we can do exactly what we want to do which is transform care so that itâs better in the future.
Naimah: Rich highlighted the importance of our relationship with the NHS in transforming patient care. Louise Fish, CEO of Genetic Alliance UK commented on the importance of joined up care following diagnosis to support them throughout their lives.
âSo, there is a lot more we need to do to work with the NHS to make sure that the care from the health service is joined up and co-ordinated for people. And then beyond that how does the co-ordination reach out to education, to housing, to benefits, to social care. The bit that almost should be simplest is if the NHS has someone who understands your childâs condition. But it should be possible for their school to be in touch and to find out how that condition is going to affect them and what support the school might need to put in place through an education health and care plan, but those links out to the other services arenât there either.
So, for us there is a lot of work to do thatâs not just around the diagnosis but itâs about ensuring that lifelong care and support is delivered in a co-ordinated way. And as more people are getting genetic diagnosis through this amazing, kind of, clinical advances how do we make sure there is also investment into the clinical services that are going to support people throughout their lives.â
Naimah: One of the key factors in supporting Genomics England to deliver this important work and all of our initiatives is the participants and the trust that they have in us. I wondered if you could share a bit more on this, so how Genomics England works with their participant panel.
Rich: Yes, so I think one of the things Iâm proudest about at Genomics England and it was established about the time I was arriving at the organisation is the participant panel who are a group of our participants who represent a broader participant across the national genomic research library. And theyâre a part of our governance, which governance sounds like a boring word, our relationship with the participant panel and their role in our governance is absolutely critical. They are the people whose data we are the custodians of, and we have a responsibility to them to live up to their expectations and also to make sure that theyâre driving the decisions that weâre making.
An example is how we setup the access to data for researchers. So, I mentioned that the way the national genomic research library works and a model that we developed through engagement with the public and with the input of our participants is that people can visit the de-identified data in our trusted research environment, but they canât take it away. They come and look at the data, they carry out their research which is on approved projects that is exploring healthcare questions. Those researchers have to go through an access process overseen by an independent access review committee that has our participants on it. So, they are making the decisions about the sort of research that they are comfortable with and that they want to be done on their data, and I think thatâs really critical.
It has also been a real pleasure to work with our participants as we design future programmes either on for example finding further answers or looking for better treatments for people who are already in the national genomic research library, already a part of our participants or to help us design future programmes, for example our Newborn Genomes Programme. Our participants as well as engagement with potential future participants and the public more broadly has been absolutely critical in guiding us on how we do that.
Itâs a team sport what weâre doing in many different ways. Thatâs with our broader ecosystem, itâs with our participants, and that means this isnât about some people going away and sort of thinking up what sounds like the right programme and using all of their knowledge and expertise and producing something which is set in stone. This is about dialogue and engagement and using that to understand the right way of us approaching the questions we are and responding to what we hear. And our participant panel are absolutely critical in that.
Naimah: And maybe it would be good now to discuss a bit about the new challenges that weâre currently facing such as AI and issues with data sharing and data protection. Can you comment a bit on that.
Rich: Yeah, so genomics is a fast moving area. Weâre really proud of the impact that weâve had already, but we also recognise that at the moment we can only use genomics in a particular number of clinical situations. And even within those we can only help a certain proportion of patients. And what our participants say to us is that we need to be restless if you like and not accept where we are today. I think itâs quite easy to merely celebrate progress but itâs really important to also then ask where we need to be going next. Iâm always guided by our participants thinking about what the new technologies are and what the different ways of approaching these scientific questions is critical.
Weâre in an extraordinary time, genomic technology has changed enormously. The power to analyse genomic data has changed enormously. These are big changes in terms of the sorts of analytics that AI could bring and the potential to work not just within the UK but with other countries and other big initiatives to make sure that weâre answering the questions as best we can. That brings with it as with all of these areas questions about how you best do things and how you balance the importance of privacy, data privacy, with the benefits of being able to look across larger number of research participants to find answers that you just wouldnât otherwise.
Likewise with AI there is the potential for us to both speed up current processes but also ask broader questions that we canât yet using some of these technologies. Doing that in conversation with our participants and the public to understand how to best balance the different benefits and also clarify where there are, sort of, very clear expectations that we shouldnât exceed is really important.
And I think thatâs one of the things that puts us in such a strong position is that confidence that our participants are guiding us and often, and speaking as a doctor myself, itâs interesting the medical community is often quite paternalistic, quite cautious and quite narrow in what they might think their participants would want. What we like to do is be driven by what our participants want and expect, and I think that has been really important for us in our history up to now as an organisation and increasingly in the future.
Naimah: Yeah, and I think youâve really highlighted how Genomics England were trying to keep the participants at the heart of everything that we do. Dr Nicola Byrne, the National Data Guardian for health and adult social care in England spoke about challenges with sharing health data and the importance of transparency and accountability in how data is used to support better outcomes from health and care services.
âSo, itâs absolutely important that people feel that they can share that information and then feel confident that any information they do share is going to be used in ways that are safe, appropriate and ethical. Whether thatâs for their own care or thinking about the benefit of other people in future through research, innovation and planning.â
Naimah: Well, letâs get back to the interview for some final reflections with Rich.
So, weâve been looking back at our achievements over the last ten years, and Iâll be keen for us to look at whatâs next. So, weâve touched on it, but letâs take some time to reflect on the research that has taken place across the global genomic landscape for example and, you know, what weâve done here at Genomics England.
Rich: The world has changed a lot in ten years. Weâve learnt a lot ourselves as an organisation and the researchers that work with our participants data and the national genomic research library have done extraordinary work. So, to give you a flavour of the sorts of things that I guess have changed in terms of what we can enable them doing in terms of research and research work. When participants data enters the research library theyâre consenting to their genomic data sitting there alongside deidentified clinical data from their longitudinal health records.
As I said through our multimodal cancer initiative weâre also now able to bring in image data for our cancer participants. And increasingly, and this is something that Matt Brown, our chief scientist, was talking a lot about at our research summit in September, was bringing in additional modalities of data alongside that.
So, for example, in our rare disease participants bringing in proteomic, transcriptomic and long read data alongside the current sets of data. It means that that resource becomes even more powerful and able to answer a broader set of questions and able to ask questions across a broader set of data in terms of what might be useful for improving the understanding of medical conditions and improving clinical care.
So, for example, there has been amazing work over the last few years on cancer and the mutational signatures that are there in tumours. For example, Serena Nik-Zainalâs group understanding the patterns of mutation that are there in tumours driven by the underlying biology, not just because it helps us understand how things have happened, but also because it helps us understand about prognosis and how to treat conditions.
Weâve got really exciting early insights from the work on the image data, that multimodal data, working as I said with academia and also looking at the work that insitro are doing. Recognising patterns between you can see down the microscope of a tumour and the genomics. To understand some of those processes that weâve just not been in a position to explore before.
And I think one of the really powerful pieces of work that is ongoing and will continue to is the ability for researchers and teams within Genomics England to continue to look for answers as our knowledge improves. So, some of the research work that weâre doing is discovering some new fields if you like of understanding. We also know that each year literally hundreds of new genes linked to rare conditions are identified.
So, enabling research that allows us to go back and look in our existing participants data to see if that new knowledge, that new knowledge about gene to condition links or better understanding of genomic variation means that we can keep looking for and finding things relevant to people who at the moment are research studies, 100,000 Genomes Project, or the Genomic Medicine Service initial testing with todayâs knowledge or the knowledge of today or whenever their test was couldnât identify because of the limitations of knowledge.
Now we can go back and identify through by sharing likely insights of clinical importance with NHS laboratories. We can then pass those findings back to participants and that has been the case in more than 2,000 of our 100,000 Genomes participants already and itâs enormously powerful. I think as we think about the direction of travel in the future, I think thinking about how we make sure that the breadth of questions that can be addressed for our participants in the national genomic research library is even broader, is really important. And thatâs, as I say, something thatâs particularly bringing in other types of data alongside has been a really important part of.
Weâre also looking to the future where as I say weâre proud of the impact that there already has been, and the NHS Genomic Medicine Service is the first national healthcare system to offer whole genome sequencing and that is extraordinary. Thinking about how we can broaden our impact is a really important part of that, and thatâs thinking about how we can be supportive of genomic technologies broader than just whole genome. So, for example, panel and exome data and thinking about some of those other modalities of data like transcriptomes is really important as well for us. And thatâs something that weâre exploring at the moment how we best do that, how we might do that.
Also thinking about the range of settings that genomics is currently playing a role and we can see a future in five to ten yearsâ time where rather than genomics being something where it plays a role in a small proportion of healthcare encounters where it could be impactful, over a much larger proportion, perhaps even up to a half of all healthcare encounters through, for example, pharmacogenomics potentially. And our Newborn Genome Programme is developing evidence that will help us understand whether that whole genome sequencing should be offered to all newborns. Potentially in research studies like Our Future Health are asking questions around the value of integrated or polygenic risk scores.
Through those sorts of elements we can see genomics playing a role much more broadly both in terms of the number, proportion of clinical settings where itâs relevant, much more towards it being a routine part of healthcare, but also across the lifetime at different stages and thinking about the value of genomic data if you like through the life course as something that can be looked at repeatedly increasingly without requiring specialist knowledge from the clinical teams so that it can have the impact it can. And thinking about how we might play a role in developing that evidence but also supporting the infrastructure through our expert knowledge in the management of coherent national genomic data sets.
And also having that dialogue in public about how genomic data might be used and working out how we generate evidence that can drive policy change. I think there is enormous potential in the future and we in the UK I think remain uniquely placed to explore those sorts of questions.
Naimah: So, weâll wrap up there and that brings us to the end of our podcast for 2023. Thanks to Rich Scott for sharing his reflections on the last ten years of Genomics England and his aspirations for the future. Moving into the new year weâll leave you with a powerful quote from our podcast with Dr Francis Collins who is renowned for his landmark discoveries and leadership in the Human Genome Project.
âMy dream Chris is that we come up with in the next decade a scalable approach to every genetic disease where you know the mutation.â
You can find all of the podcast episodes mentioned in this podcast plus many more on our website www.genomicsengland.co.uk or on your favourite podcast app. We look forward to bringing you some new episodes with more exciting guests in the New Year but do get in touch if you have any topics you would like us to cover. Iâve been your host Naimah Callachand, and this episode was edited by Mark Kendrick at Ventoux Digital. Thank you for listening.
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On today's episode of the G Word, our guests will be discussing the CanGene-CanVar programme. Funded by Cancer Research UK, the 5-year programme aims to create an interface between NHS clinical care and research that will expand genetic testing access for those with inherited cancers.
Our host Amanda Pichini, Clinical Lead for Genetic Counselling at Genomics England, is joined by Dr Helen Hanson, Consultant in cancer genetics at the Peninsular Regional Genetic Service, Kelly Kohut, Lead Genetic Counsellor at the South West Thames Centre for Genomics, and Rochelle Gold, Patient Representative on the CanGene-Canvar research programme and co-founder of BRCA Journey.
"There is also the possibility of finding out genetic information thatâs familial or inherited, which could mean that the information is not only important for the person who is being treated for cancer at the current time but also as a next step informing relatives that they might have a higher chance of getting cancers in the future due to a genetic variant..."
You can read the transcript below or download it here: How-are-genetic-tests-transforming-cancer-prevention.docx
Amanda: Hello and welcome to The G Word. My name is Amanda Pichini and Iâm the Clinical Lead for Genetic Counselling at Genomics England. We know that cancer is a very common disease. About one in two people will develop cancer at some point in their lifetime. Cancer is a disease of the genome involving many changes to a personâs genome over time as well as other factors. Only a small proportion of all cancers are inherited, but this can have a significant impact for those families who have a much higher risk of cancer and options to reduce their risk.
Today Iâm delighted to be joined by Dr Helen Hanson, Consultant Clinical Geneticist; Kelly Kohut, Consultant Genetic Counsellor; and Rochelle Gold, Patient Representative and co-founder of BRCA Journey. Weâll be discussing the CanGene-CanVar programme which aims to link NHS clinical care and research to expand access to genetic testing and care for people with inherited cancers. Welcome, Rochelle, Helen and Kelly to The G Word. Thank you for joining me today. Letâs start with some introductions. Rochelle, over to you?
Rochelle: Hi, everyone. Iâm Rochelle and Iâm one of the Patient Reps on the CanGene-CanVar research programme. I also co-founded an organisation called BRCA Journey that helps to raise awareness of the BRCA genetic mutation amongst both clinicians and the community, and also supports people who might be at risk of the mutation or who are thinking about testing, all the way through to maybe having preventative treatment or preventative surgery. We support those with that decisions. Weâre not genetic counsellors but we do basically talk to people about our experience and knowledge that we have of what itâs like as a patient to be someone living with the mutation.
Amanda: Thank you. Could you briefly tell us what BRCA is and how you came to be a patient?
Rochelle: BRCA is a genetic mutation that puts people at greater risk of breast and ovarian cancer. My mum had the mutation, in fact she had two of the mutations which is apparently quite rare. She passed away from breast cancer and just before she passed away I found out that I had the genetic mutation as well. I personally have had preventative surgery and reconstruction to prevent myself from getting breast and ovarian cancer. I got involved in being a patient rep so that I can advocate for people who may have the mutation, but also make sure that as many people as possible can be tested and be aware that they have the mutation and have that power to have the knowledge to be able to do something about it should they so wish.
Amanda: Thank you so much for sharing that with us. Kelly, over to you?
Kelly: Hello, everyone. Iâm Kelly Kohut, Iâm the Lead Consultant Genetic Counsellor at the South West Thames Centre for Genomics, which is based at St Georgeâs Hospital in London. For many years Iâve been working in clinical practice in genetic counselling, seeing patients and their families regarding personal or family history of cancer, offering genetic testing where thatâs available, and then giving the results and helping to refer people on for surveillance programmes and to discuss risk reducing options, and also help a lot with communication within families, sharing the information from the genetic test results.
For the past few years, Iâve also been doing my own research as part of the CanGene-CanVar programme, funded by the charity Cancer Research UK. This has involved partnering directly with patients and other expert stakeholders to co-design a patient website to support decision-making around the genetic chances of getting cancer in families.
Amanda: Thank you. And Helen?
Helen: Hi, everyone. Iâm Helen Hanson, Iâm a Consultant in Cancer Genetics. Iâm based at the Peninsular Regional Genetic Service which is in Exeter. In my clinical practice I see patients who either have a cancer diagnosis to consider whether they may have an inherited susceptibility or people who maybe have a family history of cancer to try and determine if they are at risk due to their family history. Like Kelly and Rochelle Iâve also been involved in the CanGene-CanVar programme for the last four years. Iâve been involved in work package three of the programme which is developing clinical guidelines with the patients who have an inherited predisposition to cancer. I was also fortunate enough to be given some funding to carry on with this work beyond the programme in the new NIHR Exeter Biomedical Research Centre.
Also, Iâm currently chair of the UK Cancer Genetics Group, who has an aim of improving the management of patients who have an inherited predisposition to cancer. Itâs been really great to work on all these different things and try and bring things together to try and improve care for patients who do have rare inherited genetic conditions predisposing to cancer.
Amanda: Fantastic. Thanks, everyone. Kelly, I wondered if you could start us off by just explaining a little bit more about how genetics and genomics is relevant to cancer. Especially inherited cancers, why is this an important thing to talk about?
Kelly: The availability of genetic testing has been increasing steadily over the years. Currently from pretty much anyone whoâs been diagnosed with cancer there should be some awareness around the possible benefit of knowing the genetics behind the development of that cancer and whether any genetic or genomic testing might help to choose more personalised treatments or surgical options for that cancer thatâs been diagnosed. There is also the possibility of finding out genetic information thatâs familial or inherited, which could mean that the information is not only important for the person who is being treated for cancer at the current time but also as a next step informing relatives that they might have a higher chance of getting cancers in the future due to a genetic variant and that they could ask their GP for referral to genetics to be offered genetic testing and to find out about their chances of getting cancer and the choices for how to manage that.
Amanda: Thank you. There are clearly some important things that someone would do differently when they know they have an inherited cancer. Helen, how can we make sure that clinicians and patients and families know what do to in these situations?
Helen: Following on from Kelly explaining the amount of genetic testing we can offer has really increased over the last five to ten years and weâre not in a position to offer many more patients genetic testing, itâs important that we also consider what to do with that information when we discover somebody does have a pathogenic variant or a mutation in a cancer predisposition gene. There are over 100 different cancer predisposition genes described and actually having a variant in one these genes is rare. Itâs difficult and like other conditions in medicine due to their rarity to really understand how best to manage these patients. But whatâs very important is that we try to understand how best we can help patients manage their cancer risk based on the lifetime risk of cancer and the particular cancers that they can develop and ensure that patients across the country are all being given the same advice, the same information about their cancer risks.
Through the CanGene-CanVar programme weâve had a whole work package which is devoted to clinical guideline development where weâve looked at a number of these genes and looked at the evidence that is available in terms of cancer risks, the utility of surveillance or early detection of cancers in that condition, and also whether risk-reducing surgery could be offered. Really try to bring together groups of experts to discuss the evidence because for some genes it really is quite limited due to the rarity of the condition. The overarching aim is really to develop guidance that is relevant and can be offered in our current clinical practice and is consistent to all patients who have a variant in one of these genes.
Amanda: You mentioned that many of these inherited cancer conditions are very rare. Is there a need to look internationally or collaborate internationally? How do you pull some of these things together when thereâs so little information?
Helen: We definitely have found it really helpful to have international collaborations. Some of these conditions there may be very few patients in the UK who have this condition, so each individual clinician who works in cancer genetics may have only seen one or two patients with the condition than themselves and, therefore, collaborating with international colleagues has been very helpful and we have recently published some guidance for a condition BAP1 tumour predisposition syndrome which increases an individualâs lifetime risk of developing mesothelioma, which is a type of lung cancer, renal cancer and melanomas of the skin and eye. This is a rare condition, but we worked with European colleagues to develop a set of guidelines advising what surveillance the patient should have, so looking to melanomas, looking for early detection of kidney cancers, so having that international collaboration has been really very helpful because in the UK there are so few cases per centre of individuals who have that condition.
Amanda: That sounds really helpful. Rochelle, we know that shared decision-making is so important in healthcare. How can we make sure that the voices of patients are reflected within these guidelines that were developing and that itâs clear to them what needs to happen for their healthcare?
Rochelle: I think itâs really important that patients are involved in the development of the guidelines, first of all, and actually within those guidelines there is stuff that talks about that, being about shared decision-making. A lot of these guidelines are in a language that are quite a clinical language that is not necessarily accessible to patients themselves. Itâs really important that theyâre part of the creation of them but also that there are things out there that enable people to understand what are these guidelines about, what do these guidelines actually mean in practice. When you find out that you have a particular genetic mutation, of course, the first place you probably go is Google. You find a hell of a lot of information and you find all sorts from different countries and different people and different organisations. Youâre like which is the thing I need to look at, which is the thing that actually tells me whatâs going on, which is the thing that really helps me to understand what this actually means for me and what should happen to me? What is the pathway for me, etc.
I think we also need to recognise that people have different levels of health literacy as well. I am someone who can probably navigate my way around a very complex system, which is the NHS, maybe better than other people. But there are plenty of people out there who this is new people, this is a completely new thing thatâs happened to them, a completely new thing to understand. If youâre not used to being part of health systems and navigating your way around it, it can be quite scary. What does mutation mean? What does it mean for me? What does it mean to my future? What does it mean for my family? All this information. There needs to be something somewhere that talks about this, some sort of lay way and helps people to understand what this means for them and helps them to engage with it. To some extent, thatâs where my organisation was born from, that thing about having somebody who can just talk about it in normal words, in normal terms and normal views of what these guidelines actually do mean. The fact is they are just guidelines, they donât tell you this is what you do. Youâre this person, youâre in this circumstance, you do this, it doesnât. Thereâs some ambiguity there that needs to be navigated by the patient and they need support in order to do that.
Amanda: Thatâs a great point. Having previously worked as a genetic counsellor, also seeing patients with inherited cancer conditions, it really strikes you how individual each personâs journey and decisions are. Theyâre thinking about all kinds of factors in their life or in their familyâs life. Navigating through that and understanding do I have surgery or do I have screening and how do I make decisions about this is based on my previous experiences and so many other factors. Having access to different sources of support to help people navigate through that feels incredibly important.
Weâve been talking a bit about inherited cancers in general, but youâre all here because youâre involved in the CanGene-CanVar programme. Kelly, could you tell us a bit more about what that is and what he programme is aiming to achieve?
Kelly: The CanGene-CanVar programme is a five year grant funded by Cancer Research UK. It involves six different work packages, so lots of experts all around the UK have been allowed to have some dedicated time to work on specific areas where there hasnât been enough resource put in in the past which has resulted in a real gap between the research and the current findings and actually using that information to benefit patients by bridging the gap and putting those research findings into clinical care.
My programme is in work package four which is co-designing patient resources which are decision support interventions. Basically, itâs a website and it can be printed as a booklet and itâs interactive and itâs up to date and itâs personalised to help convey the complicated information about genetic cancer conditions in a way thatâs meaningful and patients can understand, and it helps them with their personalised shared decision-making. The CanGene-CanVar programme is underpinned by the patient reference panel and theyâve been involved, including Rochelle and others, from the conception of the idea of the programme and all the way through with various different activities helping to look at documents as theyâre developed, before their finalised, and giving input in focus groups and one-on-one and email conversations. Theyâre called upon frequently to share their lived experience and say whatâs important to them when they make decisions and thatâs really helped to drive the direction of the research and inform the results before theyâre published.
Amanda: That sounds like a really helpful approach to developing something in a way thatâs really working very closely with patients and participants. Rochelle, it sounded like you were involved in that. Can you tell us a bit about what that was like from your perspective?
Rochelle: Itâs really rewarding, itâs really motivating to be actually one of the patient reps in relation to this. I donât want to make my colleagues from the team blush, but itâs just such an inclusive environment where as a patient is really welcomed, really heard, itâs very much a partnership and thatâs been really, really important and it makes you feel valued as a patient and actually the importance of the lived experience the patient view has really been prominent in this. I would say thatâs why itâs helped develop such a useful tool, the fact as a patient people are really valuing and taking into account our lived experience, our views, our understanding. Itâs been quite fun in some of the sessions. There have been some good debates between us and some of the clinicians and itâs been really good and really useful. I think some of the people who maybe havenât encountered a patient panel before and engaged with patientâs lived experience have probably learn a lot from it because we are pretty empowered to use our voice in this. Itâs been a really great experience.
Amanda: Iâd love to dig into those debates a bit more. Kelly, were there things that you changed in the decision aid as a result of some of those discussions or as a result of that input that maybe surprised you?
Kelly: We have made changes based directly on what weâve learned from the patients presenting their lived experiences. Theyâve been very open and honest with us. Like Rochelle, I felt so privileged to be part of this real partnership with the patients. As a genetic counsellor who had many years of experience in clinical practice before moving into this research role, Iâve been really surprised but also gratified by how much Iâve been able to learn from the patients in a different way because I am sort of taking a step back, Iâm there as a researcher and not directly as a clinician looking after someone one-on-one in clinic and just thinking about their specific needs at that time. But because Iâm hearing from people from all different situations, different parts of the UK and other countries and maybe itâs 10/20 years since they had their genetic diagnosis are actually getting a bigger picture of their care needs that we might not have heard about as the clinicians on the ground because they might not be coming back to tell us. If we havenât opened the door to that conversation about their personal situation or whoâs influencing them or whatâs important to them when they make decisions, we just might not have learned about the thing theyâre grappling with and theyâve gone off and maybe Googled, theyâve found a patient support group or something else to support them.
In my research and in my interviews and the focus groups, all of the activities Iâve been learning about the gaps in care, what might be needed to address that. The decision aid has not been yet ruled into clinical practice but weâre very keen to get it out there and everyone wants it and wants to use it. We want to make sure that weâve developed it in a robust patient-centred way as much as we can for us before we put it out. It will always be updated and go through refinements, but hopefully in the New Year we will be able to let people start using it in the real world situation.
Amanda: Thatâs great, Iâm sure youâre looking forward to that.
Helen: I was just going to add to that in terms of the guideline development weâve had a number of consensus meetings where weâve made decisions about guidelines, for example, genes that can be predisposed to ovarian cancer and weâve included patients from the patient reference panel and from other patient groups in those consensus meetings. Again, as Kelly said, thatâs been so helpful because itâs really brought something to those discussions and it is a different perspective than when we see patients in clinic because often weâre seeing them at the point of genetic testing or maybe for their results, but actually that doesnât give us that overview of the whole patient journey and the whole patient experience. I think that has been really one of the benefits of this programme and Kelly has been really pioneering the co-design of patient information leaflets, decision aids with patients. Rather than clinicians designing things for patients that we think that they will understand, itâs actually working with patients from the start to get things right the first time. Itâs been a really great part of this programme.
Amanda: Rochelle, did you want to add something further here?
Rochelle: Yes. I think one of the sessions that we had as a patient and clinician and researcher session that really stood out for me was when we started looking at how do people make decisions. We had academics and researchers whoâve looked at how do people make decisions, talk about the knowledge base and the research base that we have about it. As a larger group of patients we got together to discuss about how have we made decisions. It was really interesting because I donât think Iâve ever reflected on how I made the decision and what came from that in terms of what I did about having my mutation. Hearing about how other people did as well, that session really does stick in my mind and actually I learnt a lot as a person about decision-making theory but also about myself and reflecting on how I make decisions. So as a patient involved in this, itâs not always about what I bring to this but actually as a patient rep you get a lot from it, too. Iâve learnt a lot from the colleagues that Iâve worked with.
Amanda: Thatâs fantastic. Itâs really great to hear the careful thought thatâs gone into this, a real excellent example that hopefully others can look to. I think, Kelly, hasnât your work won an award recently as well?
Kelly: We as a whole team won an award from the academic health science network and the NHS Confederation, itâs called the Innovate Awards 2023. This was for excellence in patient and public involvement in transformation and innovation. Yes, it was a chance to showcase the really positive experience that weâve had. I think on all sides weâve learnt a lot from each other and just to hope to inspire other researchers and clinicians to take this co-design approach with patients because we all benefit from it so much. We think that the resources, the guidelines, everything that we develop will be better from the start if we work together throughout the project.
Weâre really hoping to encourage others to consider from the beginning of their idea about a research programme or clinical development to bring the patients in right at the start, because they can really help to guide where things go next and then throughout. Even through to publications being on, committees, being co-chairs, presenting together at conferences, that can all help to really share the experience and the benefits that we get from the partnership.
Amanda: Thatâs great, congratulations. Coming back now to some of the aims of CanGene-CanVar and trying to bridge that gap, as you said, between research and clinical care, I guess that means there are some needs that still arenât being met that are falling through that gap at the moment. Helen, from your perspective what are some of those unmet needs that we currently have or areas that are still needing improvement?
Helen: I think thereâs still lots that we have to learn, particularly about individual risks for patients. We might have patients who all have a pathogenic variant in a certain gene but their risks might be slightly different due to factors that can modify their risk. Trying to understand some of those risks better so that we can really have much better informed discussions with patients about their lifetime cancer risks I think would be really helpful. Work package one of the programme is really focussing on that and looking at some of the information we have through national registries and trying to understand risks for specific genes better, which will help our discussions with patients, and then we still need to understand, which is more outside the programme, more how surveillance, so early cancer detection through screenings such as mammograms or ultrasounds for different cancers can help detect cancers early. Thereâs still lots of information that we need to learn.
I think Kellyâs decision aid which has been focussed on Lynch Syndrome, I think that can be translated across lots of other genetic conditions, because for each gene there is a different set of decisions. For some of the genes that we developed clinical guidelines for we might be recommending slightly different management or for some of the genes weâve recommended maybe a minimum and an extended level of surveillance, particularly for a gene called DICER1 where weâve offered different options in childhood. Decision aids would potentially help in some of those other genes building on the work thatâs already been developed as part of the programme. Although the programme is coming to an end in the next year, I think thereâs still lots of work to be done in this area.
Amanda: It really sounds like youâve all been collectively improving how much this work is worthwhile, so thatâs great to hear. Rochelle, how about for you, are there areas that you would see as unmet needs or areas where we or research can improve to help patients and families with inherited cancers.
Rochelle: Similar to some of the stuff that Helen was saying, knowing more about what happens when people have different types of treatment, different types of surveillance and monitoring and stuff like that, I think there are things that are evolving all the time. I think in the end when you think about gaps, thereâs nothing thatâs going to be written down on paper that says if you have this, do this. In the end, every single patient is an individual with individual circumstances. I think until we actually know that if you do this, this happens and this happens, this is going to be your chances of survival if you go through this route. Even then when youâve got the chance of survival, thatâs literally just a probability, itâs not a binary this will happen or that will happen. Thereâs always going to be a need for discussion, thereâs always going to be a need for these brilliant genetic counsellors that we have to talk us through some of those complex decisions that we have to make. I think, yes, weâll get more information, weâll get more evidence, weâll get more understanding of treatments that work best for different people, and weâll get it out there and we absolutely do need to do that.
Even when you have all the information you need, even if you made a solid decision, I mean, when I found out I had the mutation immediately I was like, right, thatâs it, Iâll have preventative surgery after what happened to my mum. It was an absolute no-brainer for me. For other people it might not have been if they were at a different life stage. Iâd had my kids, I didnât need my ovaries, I didnât need my womb, it was pretty clear cut. Even then when I was thinking about the different treatment and when to have that surgery, I got most of my information from bumping into somebody in the ladiesâ toilets who has been through it before. I think thereâs always going to be a need in terms of being able to have those conversations to take in all the information you do that and make some sort of informed decision. What came out of that decision-making workshop and all the other things that we did about probabilities, itâs all just a model. Itâs a model of what might happen. The thing is, all of these models, theyâre all wrong, they just help you maybe make a discussion or a decision that might be right. You just never know. I still donât know if the decisions I made were the right decisions either. There needs to be that space for people to consider their options, youâre never going to get the definitive answer.
Amanda: An important message there. We talk a lot about using digital tools to be able to do things better at scale, better ways to give information, but I think what youâre saying is we canât replace certain elements of human connection, we canât underestimate the value of that. You made a really good point earlier as well about how so many of these decisions have uncertainty and it can be really difficult to navigate the complexities of a health system. Perhaps even more challenging if you have struggles with health literacy or if you are an underserved group in some way or another.
Kelly, I think you mentioned that some of your research has also touched on developing information for underserved groups. Can you tell us a bit more about that?
Kelly: We recognised that there are many underserved groups that are not represented in research, in literature, and applied for additional funding to do some specific targeted projects in the community. There were a couple of examples I can mention. One was inspired by colleagues at the Royal Marsden who made some videos about prostate screening and the had black men and their family members talking about this in a relaxed barberâs shop setting. Through reaching out into the community I was connected with Lee Townsend from Macmillan whoâs been making these barbershop videos around London for the last seven years. Heâs focussed on a number of topics like mental health, vaccination and cancer. We connected and it was really about making that connection in the community, him as a trusted leader, and having formed partnerships with some of the barbers who opened up their barbershops for filming these sessions and went way beyond that.
One of them has actually trained as a counsellor himself because he said men are coming for a haircut and actually they have a bald head, they donât need the haircut, theyâre coming actually for the chat. Because itâs benefitting their mental health and they felt able to open up about topics that they wouldnât talk about even at home with their family members or with their friends, such as symptoms of cancer, going for cancer screening or presenting for treatment if they were symptomatic. Itâs really powerful. Weâve actually filmed six videos with black and minority ethnicity patients, talking about their cancer experience and theyâve really both helped others by setting an example that itâs okay to talk about these things. Also, through the process an added benefit was helping themselves, so it was peer support. When they came to the barbershop to film their stories, they didnât need to stay for the whole time but they did stay for the three hours. They said afterwards how helpful it was just to hear others in a similar situation sharing their stories. One of them told me heâs got up on stage and shared his cancer journey and heâs been going to these patient groups and talking when he didnât feel able to do that in the past. Itâs been a great project and weâre going to be adding the videos to the CanGene-CanVar patient decision aid website soon.
Another thing that weâve done in the diet and lifestyle section of the website where it talks about things that people might do to lower their chances of getting cancer have partnered with Professor Ranjit Manchanda who had some colleagues in India and made some infographics that specifically depict patients of a South Asian heritage and the types of foods that they might be choosing to give examples of how they might for example try to get more fibre in their diet to lower the chances of getting bowel cancer or trying to eat more fruits and vegetables or drink less alcohol. It shows images of Indian patients. What people have told me in my research, my interviews, focus groups, is they tend to go and try to search for something that means something to them, so theyâre looking for someone like me. One of the patients I filmed she said that she had breast cancer as a young black woman and she was only middle-aged women on the websites. She thought why is this, do black women not get breast cancer or young women like me? For her to share her story was very brave but also has the potential to help a lot of other people in the community.
Amanda: Thatâs really powerful, so understanding those nuances in different cultures or communities or groups is just so crucial to really being able to also develop information or messages or provide care thatâs going to really reach those people where they are, I guess.
This has been a really fantastic conversation. If we could end with a final question, it would be great to hear from your perspective just one thing that youâd like to see in the next five to ten years when it comes to care for inherited cancer susceptibility conditions. Helen, letâs start with you?
Helen: I think that in developing the guidelines one of the things that weâve had to struggle or grapple with is a lack of evidence and the lack of the data thatâs available for some of these conditions. Iâm really hoping that over the next five to ten years that we will see much more data on cancer risks and outcomes of surveillance progress for people who have an inherited predisposition. Then we can utilise that information to be able to share with patients to enable them to make best decisions about their care. Thereâs a number of initiatives that are currently underway thinking about how we might better collect data on patients with inherited cancer predisposition in the UK, through registries, so I am really hoping that we manage to get some useful data that we can then use in our discussions with patients going forward.
Amanda: Thank you. Kelly?
Kelly: I think that over the next five to ten years as awareness and availability of genetic testing continues to increase, we know that there will be more and more families identified who have a higher genetic risk of getting certain cancers. We canât replace that personalised counselling that takes place, face-to-face or sometimes telephone and video appointments with a healthcare profession. So there are more resources needed for the NHS to deliver this. To compliment that, the patient website decision aid that we have co-designed is one way to help. What patients tell us they would like, access to a central trusted source of information thatâs up to date. Importantly in genetics itâs very fastmoving, thereâs a lot of research, guidelines are changing, and itâs very crucial to have information thatâs correct and relevant for people, and also meaningful. We can only do that by partnering together with patients and co-designing things rather than designing them and asking them afterwards if theyâre useful. Itâs a partnership all the way through that we all benefit from.
As I said earlier, itâs not a one-size-fits-all, decision-making is so personal and shared decision-making is recommended but we donât always have enough time in clinic to really address all of the issues that the patient might not have even thought about themselves. Having something like a patient-facing resource website booklet that they can look at in their own time, prepare for their questions that they really want to focus on in clinic, it might help give them the confidence to bring something up that they might not have otherwise. Itâs about a number of different ways of helping to support people. Weâve identified that there are gaps in care that we could try to help address if we have more resource in future. Those are my aspirations. Thank you, Amanda.
Amanda: Thank you. And Rochelle, to you?
Rochelle: I think for me I would like to have as many people as possible to understand or know about their genetic mutation status. We know people donât even know about the fact that they may have a genetic mutation that may make them more susceptible to cancers, and we know that even then if you do can you get access to testing to know whether youâve got it or not. That is the most important thing. My mum, if sheâd known that some of this was related, if sheâd had that awareness that breast and ovarian cancer in your family was related to potential genetic risk, maybe she would have pushed harder to get testing and maybe she wouldnât have been tested when itâs too late. In the end, all this knowledge and empowering people with knowledge, whether that be about empowering people with the knowledge that they may have a genetic mutation, thereâs a possibility of the genetic mutation, that these things are related and empowering people through the knowledge of knowing their genetic mutation status, all that is something that saves lives. From my view, it undoubtedly probably has saved my life and so my hope for the future is that we can empower more people like me and we can save more lives.
Amanda: Thank you for our guests today Dr Helen Hansen, Rochelle Gold and Kelly Kohut. If you enjoyed todayâs episode, weâd love your support. Please subscribe to The G Word on your favourite podcast app and like, share and rate us wherever you listen. Iâve been your host, Amanda Pichini. This podcast was edited by Mark Kendrick at Ventoux Digital and produced by Naimah Callachand. Thanks for listening.
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This year as we celebrated our 10-year annivesary, the NHS celebrated a significant milestone of 75 years. In this episode we reflect on our journey over the last 10 years, including the impact of embedding genomic testing into the NHS, how it all started with the 100,000 Genomes Project, and how patients have influenced the shape of the Genomic Medicine Service today.
Host Rebecca Middleton, Vice Chair of The Participant Panel at Genomics England is joined by Professor Dame Sue Hill, Chief Scientific Officer and Senior Responsible Officer for Genomics in the NHS, and Dr Rich Scott, Interim Chief Executive Officer for Genomics England in this special episode of the G Word.
"To date, weâve had over 1,500 putative diagnostic variants returned to the NHS, so to our NHS genomic laboratory hubs, for further investigation, further discussion with clinical teams. About 80% of those have been returned to clinicians and therefore to patients to, for example, give them a diagnosis or to update the diagnosis that theyâve been given or make treatments available. That is a real positive benefit from that pipeline to individual patients."
Listen to the other episodes in our 10-year series:
Shelley Simmonds, member of the Participant Panel at Genomics England, speaks to Louise Fish, CEO of Genetic Alliance UK, and Amanda Pichini, clinical lead for genetic counselling for Genomics England as they reflect on how the patient journey has changed over the last 10 years for those living with rare conditions.Dave McCormick, member of the Participant Panel at Genomics England is joined by Jenny Taylor, a valued member of our research community, and Professor Matt Brown, our Chief Scientific Officer, discussed the last decade of genomic research at Genomics England.Transcript
You can read the transcript below or download it here: Transforming-the-NHS-with-genomic-testing.docx
Rebecca: Hello and welcome to the G Word. My name is Rebecca Middleton and Iâm the Vice Chair of The Participant Panel at Genomics England. On todayâs episode, Iâm joined by Professor Dame Sue Hill, Chief Scientific Officer and Senior Responsible Officer for Genomics in the NHS, and Dr Rich Scott, Interim Chief Executive Officer for Genomics England. Today weâll be reflecting on the last ten years of genomics, including the impact of embedding whole genome sequencing into the NHS, how it all started with the 100,000 Genomes Project, and how patients have influenced the shape of the Genomic Medicine Service today. If youâve enjoyed todayâs episode, we would love your support. Please like, share and rate us on wherever you listen to your podcasts.
Thank you, Sue and Rich, for joining me today as we look back at how genomics has developed in the NHS over the past decade and impacted tens of thousands of lives. It all started with the creation of Genomics England and itâs first groundbreaking initiative, the 100,000 Genomes Project, which sequenced around 85,000 NHS patients affected by rare conditions or cancers and led to groundbreaking insights and discoveries for so many families. Iâm one of those rare condition patients and my genome sits in the National Genomics Research Library besides thousands of others. Along with the project, Iâve been on a journey over the past ten years and Iâm still hopeful that through time and further scientific discovery, my family and many others will get the answers they need for the future.
Today is a chance to reflect back over the progress of the past ten years and to look forward about whatâs next for genomics, for genomic science, the genomic service, and for the patients and families it impacts. Sue, welcome. If we can come to you first, and itâs a very big ask coming up, but can you briefly sum up your critical role in genomics over the past ten years and talk us through how youâve shaped the service in the NHS to date?
Sue: My role in genomics in the NHS has actually been much longer than ten years, because particularly genetic services have been part of the NHS journey since it was formed in 1948. As Chief Scientific Officer for England, part of my responsibility since I was first in that post in the Department of Health at that time and now subsequently in NHS England, but still with a crosscutting health and social care role, genetics and genomic services actually sit under the remit of the Chief Scientific Officer for England. Shortly after the 100,000 Genomes Project was announced and that the NHS would be a major contributor to the 10,000 Genomes Project, I was asked to lead the NHS contribution to the 100,000 Genomes Project. My role has been both of leading the NHS contribution to the 100,000 Genomes Project, and then as Senior Responsible Officer for Genomics in the NHS in introducing the NHS Genomic Medicine Service to the NHS and its subsequent role in delivery and in supporting research and other initiatives.
Rebecca: Rich, over to you. Ten years ago I believe your role was very different and you were in clinic, so how has it changed over the past decade as genomics has embedded itself into the NHS?
Rich: Thatâs right. As you say, Iâm a doctor by background and ten years ago I was consultant in clinical genetics at Great Ormond Street, where I still practice, I still do one clinic a month, but my role is primarily sat there meeting families with a child normally with some symptoms or some problems which people thought might be those of a rare condition and thinking about how we did that testing. At that time I was beginning to think about how we use in Great Ormond Street some of the newer technologies that were coming along. Using, for example, gene panels to help diagnose children who had epilepsy of early onset. Eight years ago, I joined Genomics England, where I could see the work of Genomics England and the partnership with NHS to deliver the 100,000 Genomes Project was something where at national scale we could do something, which at that stage I was just thinking about within one hospital setting. Thatâs really changed things for me in clinic, but also my role in that has changed. I joined Genomics England originally as the clinical lead for rare disease, so bringing that specialist clinical expertise to give advice on how we establish the rare disease component of the 100,000 Genomes Project.
More recently, in my role as Chief Medical Officer, Iâm actually now as interim CEO thinking about how weâve made that transition from the learning that weâve gained through the 100,000 Genomes Project to working in partnership with the NHS and Sue and team to play our role in supporting their NHS Genomic Medicine Service. The next phase, if you like, or questions for us to make sure that we are still thinking in a forward looking way about how genomics can do what we believe it can do to be really there in the mainstream for everyone in terms of healthcare.
Rebecca: And it really has been quite a journey over these past ten years, moving from a research project with 100,000 Genomes Project to a live clinical service and all the challenges that that must bring. Sue, what are you most proud of, what are those challenges that youâve had to overcome and how do you see genomics medicine service moving forwards so it can help even more families?
Sue: I think in answering your question, first of all, the Genomic Medicine Service is much broader than the whole genome sequence service that is delivered in partnership with Genomics England, and Iâll come back to that. In terms of what Iâm most proud of, I think when we started the 100,000 Genomes Project there was a view that we shouldnât involve the whole of the NHS in recruitment and in feedback to participants. I pushed really hard to have the whole of the NHS involved, recognising that if we were going to enter into a transformative project particularly for the use of cutting edge technologies by whole genome sequencing and the analytics that went alongside that, if we only started with a small number of centres we wouldnât get the transformation that was required within a whole health system.
Iâm really proud of the NHS contribution because the number of patients that were recruited over the period of time where we didnât start active recruitment until 2013 and then we completed early in 2019, to deliver this from routine care in the NHS in terms of recruitment and then for feedback I think is something that is unsurpassed by many other research projects, let alone research initiatives in genomics across the world. So while this is a world leading project, itâs also I think a world leading contribution from the NHS from its routine care position.
I was also proud myself to be a participant in the 100,000 Genomes Project within the cancer arm of the project and being able to speak at different public events around the benefits of sharing data through the National Genomics Research Library, in that itâs a benefit that is much broader than you as an individual and has the potential to impact on thousands of people.
The other thing Iâm most proud of is introducing the NHS Genomic Medicine Service because we still remain in the NHS world leading. Of course, a key part of that is that we have whole genome sequencing now available within routine care, within the NHS for patients with rare and inherited disease and cancer. Obviously not for all of those patients, but for the group of patients that fit within those broad-brush clinical groupings where there is the most need, but also the ability to deliver a diagnosis compared to what we could do from standard of care testing.
I think itâs those two halves for me with myself being a participant and being part of the NGRL right in the middle. Because, of course, from the NHS Genomic Medicine Service, which is what many other countries are grappling with, as soon as you introduce a whole genome sequencing service within a health system, how do you also continue to support research and continue to populate a research database that can be accessible, access is approved and in a safe data environment, how can you continue to support that?
Rebecca: Over to you now, Rich, on what youâre most proud of for yourself, but also for Genomics England and being the custodian of peopleâs data, that people have given their data through the 100,000 Genomes Project and they continue to give their data through the GMS. If you could pick up also on the research side, so the role that Genomics England has played in the development of the Genomics Medicine Service and the genomics within the NHS, but also in the wider ecosystem as well in terms of driving discovery and driving answers for the many families and for many patients out there who are still looking for those answers.
Rich: I think really there is one word that I come back to quite a lot which is the word together, where the journey that weâve been on as Genomics England, me playing my role at Genomics England, but all of those involved across the ecosystem, that key partnership that we have with the NHS and with our participants, but also broader than that into the other people involved in delivering a live clinical service now that we support the whole genome element of. Also, collaborators in research, whether thatâs in academia or industry, this is a team sport. What Iâm proud of most is the impact that weâve had together and recognising that when this journey started there was a real vision about the potential that genomics could bring in the coming years because of the changes that came. For example, the next generation sequencing technology, but also the changes in ability to hold and analyse data at scale. I think rightly no one would have pretended to know what the journey was.
I think the thing Iâm most proud of is that we have navigated that together. In a way, weâve continued to learn and weâve learnt from the challenges that we have encountered, whether itâs through delivering the 100,000 Genomes Project or our work since, because there always will be challenges. The reason that weâre so proud of the impact that there has been is because we recognise itâs hard to do. I think that point particularly of linking healthcare and research is absolutely key. Thatâs something that weâre working with Sue and the teams across the NHS are absolutely committed to and recognising that this is an ongoing learning area. That means learning how we do every element of it, but it also means that marrying clinical care and research is absolutely critical to getting the best outcomes for the system as a whole and for participants/patients individually.
Weâve learnt how to set up a system that works in that way. Weâve worked through the consent models that patients in the NHS receiving routine care are comfortable with. The models of presenting data de-identified for researchers to use for purposes that those participants are comfortable within, as we call it, a trusted research environment, is a model that comes with challenges in terms of the data access for researchers but is one that is really broadly accepted and we can get to work at scale. I think itâs that ongoing learning and that weâve now I think shaped an approach to genomics across clinical care and research which no one would say is perfect, but we definitely understand that weâve learnt about a model that we can keep iterating on and, crucially, weâll keep learning for participants present and future.
So that, as you say, Rebecca, one example of that situation is where families have had a test, whether thatâs through 100,000 Genomes Project or more recently through the NHS Genomic Medicine Service, if todayâs knowledge canât find the answer in terms of a rare condition diagnosis, we know that one really important element of that research offer is that researchers will continue to look for answers. If something is found that is relevant, that can be fed back to the clinical laboratories to look at. If there is something that is clinically actionable, that can be reported.
Rebecca: Thank you, Rich. I suppose, Sue, weâve had a decade of navigation, a decade of learning and a decade of adapting to really take us from the 100,000 Genomes Project to the NHS Genomics Medicine Service. There have been challenges along the way, no less weâve had COVID to deal with, a global pandemic. What other challenges have you had to overcome to embed a workable world class service within the NHS, how have you navigated that with your partners such as Genomics England?
Sue: Whatâs been really important is actually understanding the challenges. I see the challenges more in the sense of the transformation that we need to drive rather than them actually being challenges. Some of the transformation that was driven through the 100,000 Genomes Project weâve actually baked into the Genomic Medicine Service. For example, during the 100,000 Genomes Project we understood the importance of clinical leadership; particularly if genomics was going to be embedded across the NHS for patient benefit, then it would involve more clinical specialties than clinical genetics. Through the 100,000 Genomes Project, we really drove leadership and engagement across multiple clinical specialties.
We also drove this whole model that Rich talked about earlier about data sharing for broader benefit, and that benefit has then transferred over into the Genomic Medicine Service. We also recognise that if we were going to hold genome sequence a number of the processes, technical processes that happen within now our genomic laboratory hubs, needed to be standardised with quality and also external quality assurance at the core. Thatâs right from taking a sample from a patient, extracting DNA, the sequencing methodology, whatever that is, whether itâs whole genome sequencing of the type of testing within the NHS, so large gene panels, whole exome sequencing, or even smaller gene panels and other types of testing, that had to be consolidated and standardised. When results are returned we needed a standardised approach to results and interpretation. Across all of those areas if weâre trying to drive a national approach as we were in the 100,000 Genomes Project and weâre now in the Genomic Medicine Service is having an external quality assurance process that can look externally at each of those components that has been an important learning from the 100,000 Genomes Project into the Genomic Medicine Service.
A key other element of transformation, and I hope youâll agree with this, Rebecca, was the involvement of members of the public and also participants. So right through the 100,000 Genomes Projects from Genomics England establishing The Participant Panel, through to the involvement of patients and public throughout the national programme for the 100,000 Genomes Project in NHS England, through to the genomic medicine centres that we created at that time, all of that has now been reproduced in the Genomic Medicine Service. So, patient and public involvement is a key part of the delivery mechanism.
Finally, weâve had to change and continually adapt and develop the underpinning data and digital infrastructure in the NHS. Initially in the 100,000 Genomes Project we standardised the data that was collected for rare disease. We introduced the use of terms called human phenotype ontology system that enabled individual patients and their presenting characteristics to be classified; thatâs continued on into the Genomic Medicine Service. But still more work to do in the 100,000 Genomes Project, we have to get multiple informatic systems to talk to one another. As we moved into the Genomic Medicine Service, weâve both with Genomics England had to develop the analytical pipeline. Weâve had to develop a system thatâs enabled whole genome sequencing, for example, to be ordered and then to be returned after sequencing and the semi-automatic analytical pipeline in Genomics England to generate a report that could then be looked at and interpreted in the genomic laboratory hubs and returned to patients.
Whatâs been a key part of that has also been the establishment of genomic multidisciplinary team meetings that came out of the 100,000 Genomes Project, but now is embedded into the Genomic Medicine Service. Of course, the difference between the 100,000 Genomes Project contribution and now in the genomic medicine service is to ensure thereâs equity of access across the country in terms of the testing that is provided. A key part of the way in which the testing is offered is that introduction of the National Genomic Test Directory that sets out the standardised offer that will be funded by NHS England. Thatâs across where an inherited disease or cancers, as well as common diseases and some other pharmacogenomic applications.
The challenge always is standardisation, equity of access, and the infrastructure and leadership that makes this happen, together with developing a workforce that is genomically enabled so that it can spread out beyond that clinical genetics specialty into those multiple specialties to make sure that itâs embedded. So remain in terms of some of the challenges around making sure that we change clinical pathways where genomics means that we can do things much earlier on in a patient pathway and get a definitive result and intervene. This is particularly important in cancer, but itâs not just cancer, itâs also in rare disease.
Secondly, itâs about how do we develop the whole of the NHS workforce. We have 1.3 million people that are directly employed by the NHS. There are another 600 that actually are associated with the NHS through the contracts that they hold. Itâs a huge task that we still have to undertake to make sure that genomics is available to all. There are two other elements, one we have to continue to take the public with us, and I think weâve learnt from COVID that the public does understand now the importance of molecular tests. But thereâs still more to do as we use genomic information more broadly across the NHS and to drive treatment decisions that might mean that a patient thought they were going to get one cancer drug but theyâre going to get another because their genomic mutation says treatment B might be better for them than treatment A. We have and will continue to have a number of ethical issues that will arise as we consider whether itâs some of the research initiatives that are undertaken or whether itâs some of the decisions that might be made within the NHS Genomic Medicine Service or for the use of genomics.
Thatâs just a few, but it pulls it together from what weâve learnt from the 100,000 into the GMS, what else the GMS is doing, and what some of the challenges are that remain.
Rebecca: And a great deal has been done. There are a number of key challenges ahead. As you say, itâs been a learning process, itâs been a navigation process, but itâs been driven by the people, by systems, by people, and they have played a critical role and will continue to play a critical role in ensuring the success going forward. I sit as the Vice Chair of Rare Conditions on The Participant Panel. Rich, if I can come to you next, how has the patient voice, how has The Participant Panel but the wider patient voice been heard and how are their view, their needs being reflected in addressing these four big sort of buckets of challenges and how are we learning these lessons going forward thinking of the new projects? For example, the newborn genome project, The Generation Study, could you give us some examples of how that learning is going forward and weâre learning from the past but preparing for the future?
Rich: I think it comes back to one of the really key words here is transparency and transparency in a number of ways. One of those is about the fact that this is a journey weâre all on together. So, one of the things that was there right from the beginning of the 100,000 Genomes Project before I arrived was putting participants absolutely at the centre of project and the design and then in time that came for us in Genomics England wider in terms of our organisational governance. Establishing The Participant Panel on which youâre a co-chair I think was really important for us early on to make sure that participants whose data it is we hold, itâs no one elseâs data, itâs our participantsâ data, are there driving and at the centre of the decision-making process, for example, through our Access Review Committee around who accesses the data. Participants sit on various of our governance groups and thatâs a template which I think is one that people have seen in various fields as working really well. Itâs one that Sue has touched on as being looked at and has provided useful input as to how patient and participant involvement has been set up in the Genomic Medicine Service.
I think recognising that much of this is us all collectively finding the right path forward is how we approach every question that we tackle. Sometimes thatâs around really very practical questions. So, for example, Rebecca, you will know we often come to you guys about how we phrase a letter that might go out to participants, because recognising that from the inside of an organisation you see things one way but you might not recognise some of the nuances that are really important. Through to thinking about the really important questions around how we should set up access and safeguards around access that are there and, again, having participants sat on our Access Review Committee is crucial. And on to finding our way in new areas where the Newborn Genomes Programme I think is a really nice example where in many ways itâs quite similar to the 100,000 Genomes Project in that itâs a research study and itâs delivered in partnership with the NHS. Itâs asking big questions around whether genomics can be used in a particular setting and if so, how could we use it? I think a really critical part of that and one thatâs been, as you know, sat in a number of the different strands and in the overall governance for the programme, Rebecca, having participants guide us, whether those people who like yourself are already part of the national genomic research library or whether theyâre people who might join the study themselves, or whether theyâre people with a different perspective that is important to include, including that engagement work as well as just with the broader public as part of the study is absolutely crucial.
Before we even started the design of the study we set out with a public dialogue around attitudes to do with genome sequencing in newborns jointly with the National Screening Committee to understand where public views were to allow us to do a bit of a deep dive, not just a superficial vox pop view on whatâs your attitude to a one-liner question, but really to work with people on understanding some of the nuances here. Thereâs a lot of nuance in most of the questions that weâre engaging with, and then through the programme into different elements, whether thatâs designing the materials for consent or whether itâs understanding how to practically design the process for contacting families or feeding back findings as part of the study, making that part of the process rather than a separate endeavour I think is really crucial.
One of the words that I often hear people use when talking about challenging questions around how we make advantages in medicine is around explaining what people are doing. I actually think thatâs a really interesting word which I donât like. Most of the time this is about dialogue and itâs about discovering together what we are doing and itâs not people sit in with the best of intentions and with great expert knowledge in a closed room to decide whatâs the best approach, which is often an easy way to think about how to design a research study, for example, but this needs to be an active process where thereâs genuine dialogue and we learn and find our ways together.
Rebecca: Some great examples there, Rich, of how powerful the participant and the patient is in the designing future services for even more patient and participants going forward and ensuring how needs and views are reflected. But, Sue, it doesnât just happen in Genomics England, there are patients and participants across the GMSAs as well, which is fantastic to see and I sit on the panel at the East GMSA as well. How important was that for you to establish that as part of establishing the Genomics Medicine Service? How important was that for you to ensure that the patient and participant view was there locally as well?
Sue: So, I think we learnt from the 100,000 Genomes Project about the importance of patients and participants being part of the research element of the 100,000 Genomes Project and how that was designed, how the different pathways were put in place. In NHS England the patient is at the centre of everything when we come to our services. In all of our major programmes we have patient representatives, patient for an ongoing discussion with patient groups. This was both building upon what weâd created together with the Genomics England Participant Panel in the 100,000 Genomes Project, but then making sure that it fitted with the new genomic medicine service infrastructure that NHS England commissioned from 2018 onwards. It was making it a key part of that, making sure that coproduction with patients and families and really having a temperature check on an ongoing basis about the experience of patients and families of the genomic medicine service that they were experiencing has been a key component of our infrastructure and how weâve put the infrastructure together. I always think there is more we can do, thereâs more we can do to monitor the experience particularly of services. That having been said, we will continue to drive forward the involvement of patients and families in the future iteration of services, whatever that might look like.
I think if you put patients and families at the centre, that actually helps you determine the type of services that need to be commissioned nationally, the type of concerns that people have of the service and the experience thatâs feeding up, but it makes sure that patients and public representatives are part of all the important governance groups. For me, thatâs where the conversation needs to happen, it needs to happen both at an individual service level but through all the levels of governance that actually govern a service that is commissioned by the NHS in England for the population that is being served. Even if we havenât got it totally right, I hope that weâve got it as a key component of all of the services and set out in commissioning specifications such that itâs a requirement as is having the technology in place to deliver a bunch of genomic tests.
Rebecca: Thank you, Sue. The Genomic Medicine Service is unique in the way that it provides a clinical outcome that is an answer for a patient, and also includes the option of joining the research library which supports further discovery. What are the benefits of this?
Sue: The positive benefit of having the National Genomic Research Library has been through the researchers, scientists whoâve been granted access to the data. To date, weâve had over 1,500 putative diagnostic variants returned to the NHS, so to our NHS genomic laboratory hubs, for further investigation, further discussion with clinical teams. About 80% of those have been returned to clinicians and therefore to patients to, for example, give them a diagnosis or to update the diagnosis that theyâve been given or make treatments available. That is a real positive benefit from that pipeline to individual patients. But also the evidence thatâs generated enables us to evolve the genomic test directory. It enables us to add to genes if new genes have been discovered to the test directory, changes in eligibility criteria, so itâs this continuous evolving learning system. From patients providing samples and their consent for their data to be used to the research library, to the feedback loop back into the NHS that influences both individual patient care, but also the type of tasks that get offered in the genomic medicine service overall.
In conjunction with Genomics England we have also been working on an NHS Genomic Medicine Service research collaborative thatâs enabled us to look at the projects and initiatives that industry or other researchers would like to undertake, would like to have access to samples or to data, and to consider that on the basis of would this support the overall national endeavour in genomics, would it add to the National Genomic Research Library and create that learning system? Is it something that we need to do nationally rather than just locally in a research project? Itâs making the infrastructure available for those research projects over and above the ones that are part of Genomics England spending review initiatives or NHS Englandâs Genomic Networks of Excellence. But enabling us to work with industry and researchers to support their research endeavours in a way that is contained and make sure that we create and continue to create and add to the National Genomics Research Library and this overall learnings infrastructure.
Rebecca: And Rich, anything further to add there?
Rich: I think that creation, that word, that learning infrastructure is the key thing there. I think the process that has taken us here where weâve worked out how to integrate clinical care and research is so valuable, both for the individual patient and participant and also for the system as a whole, often making the choices that allow us to arrive in the direction actually all point together towards doing the same thing. Itâs really constructing things around that central vision and I think that is so important.
Rebecca: Thank you so much. Weâve had a whistlestop tour of genomics over the past decade which and improved and informed the lives of thousands of patients and families. But to finish, letâs look forward. What is your one hope for the future of genomics within the NHS? Rich, perhaps we could start with you?
Sue: I think my wish is a relatively simple one, which is that we maintain this momentum that weâve got and weâve built together. Weâre on a journey and itâs momentum towards genomics being absolutely part of the day-to-day, the mainstream of healthcare so that wherever you are in the country, whoever you are and often potentially without the clinical teams needing to feel theyâre doing anything very genomicsy, if you like, genomics is there and bound into the routine care that one has to deliver. I think when we look and we compare ourselves to other countries, because of that link that weâve made and that partnership between clinical care and research, we are in a really strong position. Itâs therefore about maintaining that momentum and getting us to that place where genomics is just a routine part of everyoneâs care.
Rebecca: And Sue, finally over to you, what is your one hope for the future?
Sue: What Iâm looking for when we put the patient at the centre is that we adopt all of the genomic technologies that would really enable us both to diagnose a genomic cause for patients that of presenting symptoms, or to inform their more preventative or inform their treatment such that genomics becomes part of everyoneâs pathway of care in the NHS, and that we really maintain the NHS Genomic Medicine Service as the most advanced service within the world and that it continues to work to populate a National Genomic Research Library with Genomics England such that patients can benefit from ongoing analysis and interpretation of their data. That we really become the leader across the world of this learning ecosystem and we give as many patients as possible a diagnosis and that we inform as many patients as possible treatment pathways. I believe weâre in the next wave of genomics following the discovery of DNA in 1953, and now itâs how do we make genomics available to everyone across where an inherited disease, across cancer, across common and acquired disease and in pharmacogenomics.
Rebecca: Thank you to our guests, Professor Dame Sue Hill and Dr Rich Scott, for joining me today. Itâs been great to talk to you and understand the journey so far and whatâs ahead for genomic healthcare. Happy 10th birthday, Genomics England, and happy 75th birthday, NHS. Hereâs to the next decade of supporting patients and more scientific research and genomic discovery to drive home. If youâd like to hear more like this, please subscribe to the G Word on your favourite podcast app. Iâve been your host, Rebecca Middleton. This podcast was edited by Mark Kendrick at Ventoux Digital and produced by Naimah Callachand. Thank you for listening.
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Genetic Counsellors play an important part in healthcare and research. This Genetic Counsellor Awareness Day we focus on the role genetic counsellors have in research, to help improve care for patients and families.
On this episode of the G Word, Amanda Pichini, Clinical Lead for Genetic Counselling at Genomics England, is joined by Emma Walters, member of the Participant Panel at Genomics England, and Jonathan Roberts, NHS Genetic Counsellor and Clinical Content Developer at Genomics England. Emma shares her personal story and our guests delve into the impact of not having access to genetic counselling. They explore how research priorities can be defined by bringing together both the genetic counsellors and what they're doing in their healthcare roles and the patients themselves and their experiences together.
Johnathan will also be talking to genetic counsellors throughout this episode from the recent World Congress on Genetic Counselling.
You can read the transcript here: Genetic-Counsellor-Awareness-Day.docx
"I think another way in which research can really push that agenda forward is understanding who isn't accessing that [genetic] counselling. So when people get through the door and they experience genetic counselling, often that can be really valuable and they can suddenly start to make sense of all this testing, this family history. They can have a chance to talk about how they feel about it."
With special thanks and acknowledgements to World Congress on Genetic Counselling and Wellcome Connecting Science for their contribution to this podcast including Genetic Counsellors, Manisha Chauhan, Alison McEwen, Jared Warde-Jospeh, Nour Chanouha, Jehannine Austin and Kennedy Borle.
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Unfortunately, please note you may be able to hear some background noise or static during some parts of the recording.
In this episode of the G Word, Candice King, Patient and Public Engagement Manager and Will Townley, Cohorts Manager who both work at the Diverse Data initiative at Genomics England, are joined by Dr Mie Rizig and Sir John Hardy, who both work at University College London (UCL).
This podcast delves into a new paper published by Mie and John in the Lancet Neurology. The paper describes a novel African ancestry Parkinson's disease genetic risk factor. Our guests discuss the need for diversity in genetic research, the key findings from their study, and opportunities for future research in Parkinson's disease.
You can read the full transcript here: Diversity-in-Parkinsons-research.docx
âThe number of people [in genomic research studies] from a white background, Northern Europeans, is about 95%. The number of people from an African background is only 0.2%. This is a significant disparity. When [clinicians] want to translate this into clinical practice, [they] think about: How will be able to test those people sufficiently enough?â
The study was conducted by scientists from the UCL Queen Square Institute of Neurology, London, the National Institutes of Health, and the University of Lagos, Nigeria as part of the Global Parkinson's Genomic Program (GP2). GP2 is supported by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF). The paper mainly included cohorts from:
The Nigerian Parkinson Disease Research Network, which is part of the International Parkinson's Disease Genomics Consortium (IPDGC) Africa, a collaboration of cohorts across 12 countries to increase the scientific understanding of Parkinson's disease in Africans. IPDGC Africa is funded in part by MJFF.The BLAAC PD study is a cross-sectional study that collects blood or saliva samples and clinical data from Black and African Americans. It is funded by ASAP and implemented by MJFF.Most of the control participants were obtained from 23andMe, a personal genetics company that has assembled a sizable cohort of individuals who have consented to contribute their data for use in various research studies. -
The Newborn Genomes Programme is delivering the Generation Study in partnership with the NHS. The study will explore the possibilities of whole genome sequencing in newborn babies, including to identify a wider range of rare genetic conditions current NHS newborn blood spot test. To do this, we have undertaken significant engagement work to identify the genetic conditions that should be looked for and fed back to families.
In this episode of the G Word, Vivienne Parry, Head of Public Engagement at Genomics England, speaks to David Bick, Principal Clinician for Newborn Genomes Programme at Genomics England. They discuss the process behind determining the provisional list of over 200 conditions caused by genetic changes in more than 500 different genes and how this list may change during the course of the study as new evidence emerges.
You can read the transcript here: Conditions-list-for-the-Generation-Study.docx
You can also find a short explainer video explaining the conditions list on our YouTube channel.
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In this episode of the G Word, Naimah Callachand, Head of Product Engagement and Growth at Genomics England, is joined by Dr Jack Bartram, consultant paediatric haematologist at Great Ormond Street Hospital (GOSH) for Children.
Dr Bartram leads on molecular diagnostics within the haematology department at GOSH and has expertise in minimal residual disease in acute lymphoblastic leukaemia. He is currently the clinical lead for haematological malignancy genomics in the NHSE North London genomic laboratory hub and has been responsible for the implementation of advanced genomics and whole genome sequencing into clinical practice at GOSH.
Approximately 2,000 children in the UK receive a childhood cancer diagnosis each year. However, childhood cancers account for a relatively small percentage (less than 1%) of all cancer diagnoses in the UK. This rarity has posed challenges in fully understanding the associated risk factors and underlying causes. In this podcast Dr Bartram discusses how genomics has emerged as a pivotal tool in enhancing our understanding, offering opportunities for precise diagnosis, personalised treatment, and improved screening methods for childhood cancer.
You can read the transcript here: Childhood-cancer-awareness.docx
"If I look back on and if I reflect on the last three years, we can probably accurately say for at least a quarter of patients it's [genomics] given us additional information, which has either aided in diagnosis or like I'd say to help re-stratify a patient or potentially reveal a target for a therapy that we didn't know of before."
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This week on the G Word, our host Will Macken, is joined by a panel of Early Career Researcher (ECR) representatives to discuss how ECRs can navigate and position themselves within the ever-changing field of genomic research.
Will is a clinician and researcher at the University College London Queen Square Institute of Neurology and Great Ormond Street Hospital. Will is also an ECR representative on the Genomics England Clinical Interpretation Partnership board. In this week's episode he's joined by:
Nicky Whiffin, Associate Professor and Sir Henry Dale Fellow at the University of Oxford, and Quantitative Genomics representative on the Genomics England Clinical Interpretation Partnership boardCharlotte Durkin, Head of Programme at the Medical Research Council, and Jamie Ellingford, Lead Genome Data Scientist for Rare Disease at Genomics England."There can be people that just pick up basic skills to analyse the dataset that's in front of them that they've spent months in the wet lab trying to generate. Through to people who are proper software engineers and will be writing unit tests to test every single line of that code. I don't think it really matters where you sit on that continuum as long as it works for you, and it aligns with your future career progressions and what you want to be in the future, essentially."
You can read the transcript here: Early-Career-Researchers.docx
You can find the information on resources, events and support for ECRs mentioned on this podcast on our website.
We've got free-to-attend monthly research seminars, and Research environment training sessions for those who have joined the Genomics England research community - find out more and register for our next sessions here.
Email us if you have any questions: [email protected].
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