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How can we bridge the gap between diverse communities?
Episode 151
Wednesday, August 28, 2024 • Duration 36:45
In this episode of Behind the Genes, we explore the challenges diverse communities face in accessing genomic medicine. The discussion focuses on issues including language barriers, cultural differences, and socioeconomic disparities that hinder marginalised communities from accessing and benefitting from genomic medicine.
Our guests delve into successful strategies for engaging these communities in healthcare research and decision-making, highlighting the importance of building trust with groups that have historically been underserved or mistreated. The episode also emphasises the need for culturally sensitive communication from healthcare professionals and how meaningful community engagement can foster collaboration and trust within genomic research.
Our host, Naimah Callachand is joined by Aman Ali, a Community Ambassador at Genomics England and Community Engagement Manager at Our Future Health, Anna Smith, Child and Adolescent Integrative Psychotherapist at Rareminds, and Moestak Hussein who works for Bristol City Council in Public Health & Communities, working directly to build and imbed cohesion, inclusion and social justice approaches in her role.
"If we talk about co-production, true co-production is really creating a power balance where there’s no hierarchy. It’s an empowering model. It empowers both the researchers or the person that comes in, but also the communities that participate, and you all start on the same level, on the same outcomes and the same goals and aims that you want to achieve."
Aman: It’s really important to engage community leaders who are really well embedded within the communities, who are attached to organisations or institutions which are well trusted in the community as well, so that we can get a wider perspective of how communities feel about genomic medicine and accessing services that we want people to engage with.
Naimah: My name is Naimah Callachand and I’m Head of Product Engagement and Growth at Genomics England. On today’s episode, I’m going to be joined by Anna Smith, child and adolescent integrative psychotherapist for Rare Minds, Aman Ali, a community ambassador for Genomics England, and Moestak Hussein, community coordinator at Bristol City Council. Today, we’ll be discussing the disparities in access to genomic medicine amongst diverse communities. If you enjoy today’s episode, we’d love your support. Please like, share and rate us on wherever you listen to your podcasts.
Aman: Hi, my name’s Aman Ali, I am an ambassador at Genomics England, a person very passionate about health research and ensuring that diverse communities are involved in health research, and I work as a community engagement manager at Our Future Health.
Anna: My name’s Anna Smith, I’m a psychotherapist. I work in private practice and also with Rare Minds, who are a company who provide therapy to people with rare and genetic conditions.
Moestak: Hi, my name is Moestak Hussein and I have a background in community development, and I’m passionate about tackling health inequalities, and building social justice and inclusive approaches to address health inequalities. I work at Bristol City Council in the public health team, and I’ve participated in the Bristol workshops around equity in research in genomics.
Naimah: So, let’s jump in and first of all I want to talk about barriers to access for diverse communities. I want to talk about how there are language barriers, cultural differences and socioeconomic factors that impact access to genomic medicine for marginalised communities. Anna, I wonder if you maybe could talk to me a bit about this.
Anna: Yeah. So, I’m talking about the traveller community, and we refer to this community as a GRT community, which is Gypsy, Romany and Traveller, so it encompasses people in the UK, people living in Ireland as well. And some of the barriers to accessing healthcare are a lack of understanding of culture. There’s been studies done where it says that people from GRT communities show up lower on all markers for poor healthcare and poor mental healthcare, and part of the reason for that is things like illiteracy. You know, you’re dealing with people who can’t read or write. They can’t read appointment times. They don’t have access to public transport. A lot of women don’t drive in this community, and also women are not very well supported within the community by the people who can drive and who can get them places, because it’s not seen as something that they need access to. Because the community is so closed, everything sort of takes place within the community.
In terms of genomic healthcare, access right from the start of life, if people are not accessing healthcare right from birth, they’re not getting the genetic testing that’s needed, so then a lot of these things don’t even show up until the illness presents itself, and then accessing healthcare from there is really difficult. You know, it’s something that – it doesn’t happen a lot. Only 67 percent of people from the GRT community were able to get a doctor’s appointment when they needed it, compared to nearly 90 percent from other communities, and that’s through things like not having a fixed address. Lots of GPs don’t offer temporary registration, which means that if you are travelling, you do not have access to a GP, which is your first port of call if you need any access to healthcare. So, many people from the GRT communities are using A&E services in order to get healthcare, which – you know, they are not set up for dealing with long-term life changing conditions. They’re there to deal with what’s right in front of them and then they move on. There’s no sort of continuity of care.
Naimah: Thanks Anna, that’s really highlighted a lot of barriers for the GRT community. And I wonder, Aman, if you want to come in now and maybe discuss some of the barriers that maybe the Muslim community might experience.
Aman: Yeah, I think anyone involved in medicine or anyone who’s a doctor is really well respected in the Muslim community. That profession is something that every parent aspires for their children to get involved in. They at least want one of their children to be a doctor. Having said that, there’s this willingness to engage with the space, but there’s a lack of knowledge, which is a huge issue here. People don’t know what the word genomics means or genes, or understand DNA. Some of this language is a huge barrier to understanding and then eventually accessing some of the services that could be available to people from Muslim communities. Because when we speak about Muslim communities, we’re talking about a huge, diverse group of people from South Asia, from North Africa, from the Middle East, and they all have their nuances and different cultural experiences as well.
Just to kind of point out maybe one or two, most people in the UK have grown up in the UK, where access to healthcare is free, whereas this is quite a strange phenomenon for people who may have not been born in the UK and then access healthcare services in the UK. And the context being here is usually they pay for healthcare in other countries, and whenever any public or free healthcare is provided, it’s usually seen as kind of not very good or suboptimum, or yeah, it’s not going to be very helpful for us. So, when they see free healthcare in the UK, there’s that kind of apprehension, “Actually, is this going to be worthwhile? I’m not paying for this, so it’s not going to be very much good for me.” So, those are some of the cultural nuances that certain communities where healthcare is not for free in certain countries that poses a barrier.
Language in terms of speaking and reading is an issue. So, a lot of people, they may speak a language, but they don’t know how to read a language. So, even when services are translated – I, for example, can speak Bangla, but I can’t read or write Bangla, and not a word of Bangla at all. So for my parents, who can speak Bangla very well, their reading level is actually quite good, but I know that many within the community, they didn’t get education back home, and therefore reading and writing is a challenge as well. And then you have the issue of dialects. There’s so many dialects within so many different communities, so when a language is spoken or written in a particular way, if that dialect isn’t your mother tongue or a dialect that you’re familiar with, then that causes challenges to access as well.
Naimah: Moestak, how do cultural beliefs and values influence attitudes towards genomic medicine within each of these different cultural communities?
Moestak: I think Aman and Anna touched on it a lot, and it’s about communities being able to coproduce that historically hasn’t been there. The supremacy of certain communities to have a voice and be able to express how they would like to shape their healthcare, but also access to healthcare barriers have been part of having a barrier in access. And I think Aman touched on like even the term genomics, I don’t think it exists in particularly my community. I come from the Somali community, and I’ve tried to look at historical kind of words and terms. I mean, our language only got developed in 1973, the written language, so you can imagine that there’s a lot of gaps or there’s other terminologies.
So, the cultural beliefs and values is also communities’ recognition to be driving their own health needs and priorities is not valued within those sectors such as healthcare. I mean, we’re still talking about holistic medicine. People go to their faith leaders in the first instance to have support around prayer. That’s not necessarily recognised by mainstream health provision. And I think it’s about how do we build on those strengths and how do we recognise that that is a really great part of communities. And it’s also tradition and customs within childbirth, from birth, understanding what children and young people and families will need. I know there’s customs and traditions for women to stay at home, for example, for 40 days, and those are the kind of traditions that could be built on. And I think it’s about making sure that the child doesn’t pick up bacteria or things like that.
So, there is an understanding and knowledge within communities of genomics. It’s the awareness and the training around patient centred approaches are still missing, in my opinion. And I think that influences how people view genomic medicine. It goes back to the lack of trust and historic past abuses and cases, that communities has resulted in lower participation and a reluctancy to be part of genomic testing, but also that lack of understanding.
Naimah: Anna, did you have something you wanted to add in there?
Anna: What you were just saying about keeping it within the community, that’s something that we see with the GRT community massively is everything is handled within the family, and I think that’s not necessarily valued outside of that community. If you arrange an appointment with someone and the whole family turns up, it’s like, “Woah, what’s going on here? You know, how is this managed?” And it becomes a safeguarding issue, when actually that is how it's managed, and very often you need to get the whole family on board before you can start working with an individual. Because within the GRT communities, individuals do not exist outside of their families. Even what we’re saying about language, a lot of the GRT community who live in England now speak English, but the words that they use for mental health are very different.
You talk about mental ill health, that translates as psychosis in the GRT community, whereas if you’re talking about depression and anxiety, somebody might say that they’ve got bad nerves. So, if you come up and say, “We’re dealing with mental health now,” people would say, “Well, I don’t have psychosis, I don’t have that, this is not an issue for me.” And it’s like you’re speaking different languages even though you’re using the same words.
Naimah: From what all of you have said as well, it does sound like there are a lot of similarities in the barriers in each of the different cultural communities.
I wanted to move on to ask about what strategies have been effective at engaging these diverse communities in healthcare research and decision making processes.
Aman: There are a number of ways I’ve seen best practice take place in regards to kind of community engagement. The approaches have been one of two approaches. One, either inviting the community to come to your spaces, i.e. organising events or having opportunities where people can engage with your service. Or the alternative approach, which I think is actually more effective, is actually going to the spaces where communities are most familiar with. So, whether that’s holding a focus group at a community centre, at a church or at a mosque, or engaging in coproduction with a community organisation, to come together, to come up with an idea of how to best engage communities. And I also feel like there’s a difference between PPI, patient and public involvement, versus community engagement.
And those are the two major approaches that I’ve seen when it comes to community engagement, and I’m a big advocate of community engagement, because you’re going into spaces which are authentic to the very communities that we are hoping to engage, but you’re going into an unfamiliar environment as opposed to bringing that community into an unfamiliar environment, where they might be a bit guarded with what they want to share and how comfortable they feel. So, those are some reflections on good practices in community engagement.
And I think one of the key things that we need to do is understand who are the key community leaders within that community, ‘cos it’s one thing being within that community, and being able to speak about that community are two different things altogether. So just to articulate what I mean by that, I live in Luton, but I’ve just moved to Luton two months ago, so if you ask me about what life is like in Luton, I’ll be able to speak about my experience, but if I was to live here for 20, 30 years then I’d be in a better position to speak about how people in Luton live and what their experiences are like, and that’s two different perspectives you’re going to get. So, it’s really important to engage community leaders who are really well embedded within the communities, who are attached to organisations or institutions which are well trusted in the community as well, so that we can get a wider perspective of how communities feel about genomic medicine and accessing services that we want people to engage with.
Naimah: Thanks Aman. I think you made a couple of really good points there, and I think you kind of have this overarching feeling of building trust, which is what Moestak mentioned in the previous question as well. I thought maybe now would be a good time to discuss your first responders project, Aman, if you could tell us a bit about that. It’d be good to hear the kind of developments from that community work.
Aman: Yeah, so one of the ideas that came about from engagement actually that we had with some community leaders within the Muslim community, primarily some imams, they heard about the work of Genomics England, they heard about the work of research in particular, and they were really keen to get involved even further, but they were honest in saying that, “I know very little about this space. And it’s one thing for me not to know much, but then if I don’t know anything then I’m not able to then advocate for this within the community. So, two things you need to help me with. One, help me understand this space, but also allow me to then be able to advocate for services or information that my community can benefit from.”
So, that’s where the inception of this first responders idea came about. The idea being that community engagement happened with some imams from all across the country, where we trained them to understand a bit more about genomics, and genomic healthcare and medicine, but also to be able to navigate a number of scenarios that they may face in the community. For example, there’s a mother who has been recommended by their GP to go see a genetic counsellor, but they’re really worried about broaching that conversation with their husband or their family, because of the challenges that they may face. So, how would you support someone in the community when that scenario comes up? Or for example, someone like Genomics England or Our Future Health or another organisation has approached you about a research study, and they want to engage your community, how would you have that conversation with that particular organisation, advocate for those health programmes within your community?
So, we just presented a number of scenarios. But I think the main thing that we ended with was giving the imams in this particular incident the ability to signpost to services, be it helplines that are available for communities to access more information, or websites that people can access in order to understand more information about different issues to do with health conditions, or whether it be better understanding issues like cousin marriages or kind of accessing genetic testing.
Naimah: That sounds like you’re empowering the leaders to advocate for healthcare and share this with their communities through this work. I wonder, Anna, is that something that you could do in the GRT community as well, like empower the leaders of the family to disseminate these healthcare messages, and how would we do that?
Anna: Yeah, I think so. I think a lot of it would need to be outreach, and there are people out there who can help bridge that gap. For example, there’s a great team called Family Friends & Travellers, and if you get in contact with them and let them know which community you’d like to go into, they can help arrange, or they will come with you to go into that community. Because the GRT community, you know, is very mistrustful of anyone coming in, and rightly so. It was only in 2011 that they were included on the national census as an option to say you’re from that community, so I think there’s massive mistrust there of anyone coming into the community.
So, if you want to engage the leaders of the families or of the communities, you’re going into a settled traveller site, there will usually be somebody who is in charge of that site, not officially, but maybe their family might be the biggest family or they might be the most important family. And there are people out there who will allow you to start to engage with that person, who can then disseminate the information. But it needs to be outreach care, and the information that you disseminate, it needs to be tailored to people who have left school at primary age, who don’t have the skills to read or write, or to manage appointments or read prescriptions, or have access to that type of healthcare. That’s where it really needs to be tailored.
And I think confidentiality as well needs to be tailored a lot, because gossip and reputation and shame is huge in the GRT community, and if you are seen to be engaging with someone outside of the community, that is something that can bring a lot of shame to you and your family, so it needs to be handled really, really carefully.
Naimah: Just to kind of go along with this theme of trust that you’ve all now mentioned, Moestak, I wonder if you could maybe comment on what strategies can healthcare organisations and researchers employ to build trust with these communities who have historically been underserved or mistreated?
Moestak: Yeah, I think I mentioned earlier about the hierarchy of power around superiority and also mistrust of medical professional generally, and I touched there on how safeguarding concerns are triggered on not understanding cultural norms and practices within communities, and misconstruing that with safeguarding. There is generally that mistrust is there. And I think what Aman touched on there is really the importance of asset based approaches, and really building on transparent and really embedding transparent and inclusive practices from the onset. I mean, if we talk about coproduction, true coproduction is really creating a power balance where there’s no hierarchy. It’s an empowering model. It empowers both the researchers or the person that comes in, but also the communities that participate, and you all start on the same level, on the same outcomes and the same goals and aims that you want to achieve.
And I think it’s important to embed those kind of approaches, and it’s Covid-19 – I mean, we took part in Bristol in King’s Fund research around the community champions model. It’s exactly that, about engagement, about community driving their own solutions, and being able to collectively collaborate, drive their health piece forward, but also increase the capacity of communities. We worked with clinicians who come from those communities, and it’s no surprise that the uptake of covid-19 vaccine increased as a result of working with those trusted voices.
Quite often, those really effective programmes and engagement often are not funded adequately. They’re not sustained. And what happens is that we constantly are having to rebuild and restart, and that really does affect trust as well with communities. And when something works, why not build on it? And even now with that Covid-19 learning from the community champion model, the resource is not there anymore. It’s not valued anymore, sadly. That in itself is a risk, I think, in building the trust, but also the strength to continue that work and adapt in other ways around genomic medicine, and even increasing and diversifying the genomics data pool, helping communities understand and drive that. And that first responders project, communities being trained to capacity build and then being able to drive that within their communities, that’s the only way that we’re going to have effective strategies.
Aman: I think adding onto what’s been mentioned, with regards to building trust, it’s really important to understand the motivations of communities, and to understand what messaging is going to resonate with different communities, and it’s going to be a different message for each community. You can’t have the same approach for all communities. A recurrent theme that I’ve come across when engaging different communities is this difference between messaging which is individualistic and then messaging which is about the community and more the collective message, and how that resonates a lot more with certain communities that I’ve engaged with, particularly within Muslim communities. And that’s something that I think is a bit untapped in regards to kind of any materials that are created, be it posters or videos or any content looking to reach out to communities.
When we did some focus groups with some communities in Watford, who are primarily from the Pakistani community but also other parts of Asia in that region, the biggest response or biggest positive response that we got was when we posed the question, “If you were to know that people who look like you, from wherever your parents are, family may be from, would you be motivated to take part in that research?” And the biggest yes came on the back of that question. And that speaks to the fact that, “If I know that my family or my community, not just in the UK but abroad can benefit, then that would really motivate me and build trust that actually you’re not just here to benefit me as an individual, but you’re here to benefit my community as a whole, and therefore, yes, I’m going to be more trusting of this programme and be more motivated to take part.”
Naimah: I just wanted to go briefly back, Moestak, you mentioned cultural norms, and I wanted to talk about the cultural norm in societies where maybe people may marry someone from the same ancestor, and what the societal fallout from these practices might be.
Moestak: The stigma and the stereotypes often for communities comes from those beliefs and messages that are often sometimes not even backed up with scientific evidence. It can be seen as Islamophobic sometimes of Muslim communities that practice that. But also I think what’s important to understand is that concept around hereditary conditions and how that can determine one’s health, and it’s not really fully appreciated or desired. And so as a result, for example, a lot of people refuse to even have those early onset maternal testing for the foetus. My personal experience, I have three children, teenagers now, and I refused those tests as well, because my belief and my religious beliefs would kind of not align with being able to terminate a foetus if there were some genetic conditions. And so I think that is often not understood and made very clear to communities, and build on their beliefs and attitudes and values. And so those are the kind of cultural norms that are not fully understood.
But also the opposite side of that actually around being able to prevent a good life for somebody or a bad life for somebody, and being able to prevent genetic conditions is also part of the religion on the flipside, but again it’s not creating that link. That cultural beliefs is not understood. I think also the community implications around the stigma. I mean, autism’s a big issue in the Samali community, and I remember years ago when I was working in education, we had a big issue around even acknowledgement of diagnosis and referrals, and it’s because of the stigma. Those perceptions do exist within communities that if someone has a genetic condition or ill health or a disease, it’s almost like being a black sheep in the community. And so it’s being able to build on those desires of the community wanting to be healthy and well, I think is not often understood.
Naimah: And do you think it’s partly as well education of healthcare professionals to communicate in a really culturally sensitive way?
Moestak: Yes, exactly, that’s exactly what it is. It’s missed opportunities really that we can build on. In that particular example of autism within the community, I was able to do a really positive piece of work with the community, and building on their interest and their skills, but using my own lived experience and understanding and knowledge, and being able to inform that within education sector but also the health sector, and providing that training and upskilling. And there is unfortunately a lack of diversity within the workforce if you look at the NHS. The lower level kind of cleaning and porter staff are ethnic minorities. And so it is about using those clinicians, as I mentioned earlier, that are coming from those communities are the forefront.
We’ve recently had a really positive piece of work in Bristol around let’s talk about MMR, and we had a cohort of unvaccinated community, a Somali community, young people between the age of 16 to 25, and we worked with a Somali clinician, who led on that piece of work, and it was absolutely amazing. The young people as a result trusted her information and took up – but again also another thing that’s important is that a lot of data in the medical system is missing. I for one migrated here from the Netherlands, where I came there as a refugee at the age of three years old. My medical history is completely missing in both the UK records but also in the Netherlands, so I didn’t know if I had MMR vaccine. So, it’s a lot of gaps in information that people have, newly arrived communities that still need to constantly be updated and informed and education awareness raised with those communities.
Naimah: Anna, I wonder if you wanted to add anything onto that point.
Anna: It’s really difficult with that mistrust and sort of how closed the GRT community is to getting that information in, and I think to getting that information understood as well and to make it seem like it’s important. Because family is the most important thing, people are accepted the way that they are. You know, if we’re talking about autism, people are accepted the way that they are, and it is a bit like, you know, “There’s nothing wrong with my child, how dare you suggest that there is?” That testing isn’t done because the access to healthcare is so difficult, because people can’t register with GPs, because they can’t access maternity care, they can’t access postnatal care. Because they can’t register with the GP, they’re not on the system, and then the records don’t exist. Still now there’s birth records and death records that do not exist for these people within the communities, never mind medical history throughout their lives.
Naimah: I think it really highlights a lot of gaps, doesn’t it? Aman, do you want to add anything to that question?
Anna: Your opening remarks is that it’s a cultural norm in all societies, and we see even within the royal family in the UK, that it seems to be that any disparaging comments are targeted towards certain communities, and even then unfairly. I mean, often it’s associated with Muslim communities, but I would say the majority of Muslim communities don’t practice marrying someone from within the same ancestor. It’s certain cultural communities who do practice this. Having said that, even that practice shouldn’t be seen in a disparaging way, because it’s how those communities live their lives, and so we should be respectful of that and not speak in any way disparaging towards that community. And I think we have responsibility – ‘cos obviously nationally the conversation then moves onto increased risks of genetic disorders, and so we should be very matter of fact about what the percentage increase is when it comes to the likelihood of genetic disorders within families who marry with the same ancestor.
Because what happens is, if we’re not very clear with what the actual facts are with regards to the increased risk of genetic order then even within the community which practices marrying someone from the same ancestor, that figure can be inflated, and so this perpetuates fear and perpetuates the stigma even more. Whereas if we are just matter of fact, “This is the increased risk of genetic disorders,” and leave it there, then the communities can decide and they’ll have a more informed position. I think the figures are an increase from two to six percent increase, but if you were to ask people within the community, “What’s the increase of genetic disorders if you’re marrying someone from the same ancestor?” they might think it’s 40 percent or 50 percent or a really high figure. So, that’s something that we need to work towards better understanding, which will lead to removal of that stigma as well.
Anna: Again, that’s something that we see in the GRT community as well, there’s been research done by a woman called Sally Anne Lynch into cousin marriage within the Irish travelling community, and when they tested people, they found more than 90 genetic conditions that are present within people’s DNA within that community that just aren’t tested at birth. And I think, you know, you’re right, it’s something that is not talked about, because outside of these communities it’s seen as wrong and it’s not seen as something that’s normal. It’s seen as abnormal. But within this community, it is very normal and it’s very accepted. But then the testing isn’t done because of the access to healthcare.
Naimah: I think it just seems like it does kind of boil down to education and educating healthcare professionals that it is kind of normal practices. Aman, did you want to add something else?
Aman: Yeah, Anna made a really good point about testing. I think there’s something that is a gap in the service that we probably don’t provide more widely is that, when it comes to people who practice marriage within the same ancestor in other countries, testing is very normal. So, I know there’s many countries around the world where it’s very standard practice and even a requirement in certain countries that you must be tested before you get married, and so maybe that’s something that we can learn from in the UK.
Moestak: I think it’s important to understand that some communities, decision making of consent is sometimes done by the head of the family, and I think that that is not fully understood as well, and often can be a barrier to participation. And I think that there’s an element of empowerness that is needed, particularly around women that need that empowerment model around consent of decision making around their testing and genetic testing, and just medical consent.
Naimah: That’s an excellent point as well, thanks Moestak.
So, I know we’ve touched on aspects of this already, but I wanted to finish on this question, how can meaningful community engagement foster trust and collaboration in genomic research and healthcare initiatives?
Aman: I think one of the things that I would really improve is just awareness around genomic healthcare and genomics in general. It’s a learning curve that’s going to happen within communities at different rates, and we need to be mindful of this because that rate will determine also health inequities that are experienced by those communities as well. So, we need to make sure that we are adequately approaching all communities to the best of our abilities. Having said that, target maybe more resourcing and educational opportunities for communities which have been underrepresented in health research and in genomic health research as well primarily, so we need to sort of prioritise certain communities in regards to our community outreach, because then we’ll dispel any myths that people might have and work towards chipping away at the mistrust that certain communities may feel towards just healthcare in general, but more particularly about genomic healthcare, ‘cos genomic healthcare brings up some unique challenges and some unique perspectives within communities.
So, there’s a number of fears about the future, but also misgivings about healthcare in the past as well that we need to acknowledge. So, by having community engagement initiatives, which are prioritised from the beginning and not just an afterthought, we can go a long way towards getting over some of the challenges of the past, but also not making new challenges for us in the future.
Anna: I think as a whole, the UK has got a long way to go with building trust with the GRT community. I think it’s going to take some time. They still are one of the most marginalised communities. For example, in the area that I live, there was a GRT funeral going on a few weeks ago, and all the pub shut because they didn’t want GRT communities in their establishments, and there is no other community or minority that that would happen with now. So, I think there is still quite a long way to go to gain the trust of the GRT community. And in terms of healthcare, I think we need to go right back to the start and learn about these communities, and understand their cultures and their practices, and how they work without that judgement. Living a nomadic lifestyle is still criminalised. There needs to be a decriminalisation around these communities before we can even start to begin to work out how to go there and allow them to access healthcare and knowledge and information around genetic conditions, and around health and mental health.
It’s going to be a very long road from here, but I think what we can start doing is to start that destigmatisation. If you are a doctor and somebody turns up in your surgery identifying as someone from the GRT community, understanding the background they come from, and not having all those prejudices, you know, which is very difficult to do, to get rid of those thoughts that you already have about someone. I think we need to make a real effort to start, and I think there needs to be changes within the NHS in order for people to access healthcare better. I think the resources that are given and the information that goes out needs to be more specifically tailored to these communities if that’s who you’re trying to engage with, because there’s so much that goes on in the community that’s not known outside of the community, and it’s not spoken about, and within different GRT communities as well. You know, there are different GRT communities all around the UK, and what goes on in them is not known to other GRT communities either.
So, it’s about being specific with the information that you’re getting out, with who you’re actually targeting. And I think a bit like we were saying earlier, it’s the women, you know. The women have childcare responsibilities almost all of the time, and they are the ones who bring up the children, but they’re not necessarily the ones that make the decisions about the children or the child healthcare. You know, women are expected to do jobs in the morning. Women are not available before 11 o’clock in the morning. So, think about when you’re making appointments for. Think about when you’re going. I think it is going to be a long, long road before we get there, you know, with building trust and getting the information out there, but I think we can make a start.
Naimah: Yeah, it does seem like there is lots of ways we can start tackling it slowly. Moestak, I wonder if you had anything you wanted to add.
Moestak: As a public health specialist, you know, we’ve not been taught genomic medicine or genomic health at all in terms of how that can benefit and radically change the NHS and improve determinants of health, so that’s a massive gap of knowledge within the healthcare sector and professionals. But I think in terms of addressing the historic mistrust, I think there needs to be an acknowledgement and a real openness around the historic, you know, abuse and unethical practices that have existed within health. There are other countries that are much more advanced in that and really embedding that within communities through pledges. That long-term kind of piece of work for me is missing. You know, it’s that wider education piece that’s missing that needs to be really embedded in the culture.
But I think also investing in the infrastructure in the community. Like far too often, if the long-term vision is not there, communities are reluctant to get involved and have trust within that, so I think that’s an important part as well. And I think it’s also about demonstrating the benefits of genomic medicine. I think that needs to be done in a community level way, through storytelling. I know that there’s now a lot of development around cancer treatments around genomics, but I think it’s about having those people who have those lived experiences from different communities to be able to share the benefits and demonstrate that through their way, and being appropriately reimbursed as well. I think that’s really important.
I think generally, I think there’s a long way we’ve got to go. I’ll never forget when I went to Vancouver on a conference around health, and there was a lot of reconciliation there, where there was really acknowledgement, and the indigenous communities there that have a lot of health disparities were able to kind of overcome some of that and start building as a community and addressing tackling health inequalities because that trust was built and that acknowledgement from high up, from government level, all the way trickled down to local. I think also patient centred approaches around – like we mentioned, we talked about linking the cultural norms and the values and the beliefs that people have, and the skills and the assets that they have to be able to lead on these solutions themselves, that really needs to be embedded to build trust.
Aman touched on the perception around what could be done with genomic data. I don’t know if Aman wants to elaborate a bit on that, but that’s really important. It’s a big barrier. It’s how do we create transparent ways of storing data, but also use various ways of communication. It doesn’t have to be traditional reports. It could be through podcasts. It could be like community messaging.
Naimah: Yeah, I think that’s a really important point. Aman, did you want to come in on that?
Aman: Yeah, I think sharing the stories of the past in an appropriate setting, in an appropriate manner as well – ‘cos it’s a bit of a double edged sword, ‘cos you don’t want to scare people who are unfamiliar with these stories, but at the same time there’s a moral responsibility for all of us involved in this space to speak about these issues, one from the perspective of acknowledging what’s happened in the past, so then people feel like, “Okay, you’re not trying to hide anything here,” but from the perspective of also that we need to make sure that we don’t repeat some of the mistakes in the future, and that as people involved in genomic healthcare and involved in this space, that we’re cognisant of these misgivings in the past, and we’re cognisant of our responsibility to safeguard communities in the future.
Naimah: Okay, so we’re going to wrap up there. Thank you so much to our guests, Anna Smith, Aman Ali and Moestak Hussein for joining me today as we discussed the barriers to access to genomic medicine for diverse communities, and the impact it has on these communities. If you’d like to hear more like this, please subscribe to Behind the Genes on your favourite podcast app. Thank you for listening. I’ve been your host and producer, Naimah Callachand, and this podcast was edited by Bill Griffin at Ventoux Digital.
Can genomic testing prevent adverse drug reactions?
Episode 150
Wednesday, August 14, 2024 • Duration 36:49
Pharmacogenomics plays a critical role in personalised medicine, as some adverse drug reactions are genetically determined. Adverse drugs reactions (ADRs) account for 6.5% of hospital admissions in the UK, and the application of pharmacogenomics to look at an individuals response to drugs can significantly enhance patient outcomes and safety.
In this episode, our guests discuss how genomic testing can identify patients who will respond to medications and those who may have adverse reactions. We hear more about Genomics England's collaboration with the Medicines and Healthcare products Regulatory Agency in the Yellow Card Biobank and our guests discuss the challenges of implementing pharmacogenomics into the healthcare system.
Our host Vivienne Parry, Head of Public Engagement at Genomics England, is joined by Anita Hanson, Research Matron and the Lead Research Nurse for clinical pharmacology at Liverpool University Hospitals NHS Foundation Trust, and Professor Bill Newman, Professor of translational genomic medicine at the Manchester Center for Genomic Medicine, and Professor Matt Brown, Chief Scientific Officer at Genomics England.
"I think we’re moving to a place where, rather than just doing that one test that might be relevant to one drug, we’d be able to do a test which at the same price would generate information that could be relevant at further points in your life if you were requiring different types of medicine. So, that information would then be available in your hospital record, in your GP record, that you could have access to it yourself. And then I think ultimately what we would really love to get to a point is where everybody across the whole population just has that information to hand when it’s required, so that they’re not waiting for the results of a genetic test, it’s immediately within their healthcare record."
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 visit Unique's website.
"Although we’re a group supporting families and patients, actually a big part of what we’re doing is around translating those complicated genetics terms, and trying to explain them to families, so they can understand the testing they’ve been offered, the results of testing, and really what the benefits and limitations of testing are...just knowing why it’s happened, being able to connect with others, being able to meet others, but actually often it doesn’t necessarily change treatment."
In this explainer episode, we’ve 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 you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk.
Naimah: What is the difference between DNA and RNA? Today, I’m joined by Clare Kennedy, who’s a Clinical Bioinformatician here at Genomics England, who’s 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.
Hope for those with "no primary findings"
Episode 139
Thursday, March 14, 2024 • Duration 44:12
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 it’s also really important to add that hope isn’t necessarily lost when you don’t 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 SWAN's website.
In this explainer episode, we’ve 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 you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk.
Naimah: What is a variant of uncertain significance? Today I’m joined by Helen Brittain, who’s 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, I’d 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 they’re spelled out and structured, so that the body can understand them and make sense of that instruction. A variant is where there’s 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?
Treating Mila - Lessons for those living with rare conditions
Episode 137
Wednesday, February 28, 2024 • Duration 45:44
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 Mila’s 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 it’s a fatal or life-longing debilitating or difficult disease, if you know that what’s being learned from your child both from just the genomics to the potential treatments that’s helping the next child, that helps parents like me be able to continue living."
In this explainer episode, we’ve 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.
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.
Celebrating genomic breakthroughs - Insights from the Festival of Genomics
Episode 135
Thursday, February 15, 2024 • Duration 36:27
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 they’re 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, it’s about treatments, but it’s 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 you’ll need throughout your lifetime."
In this explainer episode, we’ve 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 you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on info@genomicsengland.co.uk.
Naimah: What is a rare condition? Today I’m joined by Ana Lisa Tavares, Clinical Lead for rare disease research at Genomics England, and she’s going to explain more.
Ana Lisa: There are thousands of rare conditions. I hesitate to say a number as we’re 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 that’s 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 isn’t one single universal definition.
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Want to learn more about personalised medicine? Listen to our Genomics 101 episode where Professor Matt Brown explains what it is in less than 5 minutes: Genomics 101: What is personalised medicine?
Bill: What we’ve seen is that the limited adoption so far in the UK and other countries has focused particularly on severe adverse drug reactions. They’ve been easier to identify and there’s a clear relationship between some drugs and some genetic changes where that information is useful. So, a good example has been the recent adoption of pharmacogenetic testing for a gene called DPYD for patients undergoing cancer treatment, particularly breast and bowel cancer. And if you have an absence of the enzyme that that gene makes, if you’re given that treatment, then you can end up on intensive care and die, so it’s a really significant side effect. But as you say, the most common side effects aren’t necessarily fatal, but they can have a huge impact upon people and on their wellbeing.
Vivienne: My name’s Vivienne Parry and I’m head of public engagement at Genomics England, and today we’ll be discussing the critical role of pharmacogenomics in personalised medicine, highlighting its impact on how well medicines work, their safety, and on patient care. I’m joined today by Professor Bill Newman, professor of translational genomic medicine at the Manchester Centre for Genomic Medicine, Anita Hanson, research matron, a fabulous title, and lead research nurse for clinical pharmacology at the Liverpool University Hospital’s NHS Foundation Trust, and Professor Matt Brown, chief scientific officer for Genomics England. And just remember, if you enjoy today’s episode, we’d love your support, so please like, share and rate us on wherever you listen to your podcasts.
So, first question to you, Bill, what is pharmacogenomics?
Bill: Thanks Viv. I think there are lots of different definitions, but how I think of pharmacogenetics is by using genetic information to inform how we prescribe drugs, so that they can be safer and more effective. And we’re talking about genetic changes that are passed down through families, so these are changes that are found in lots of individuals. We all carry changes in our genes that are important in how we transform and metabolise medicines, and how our bodies respond to them.
Vivienne: Now, you said pharmacogenetics. Is it one of those medicine things like tomato, tomato, or is there a real difference between pharmacogenetics and pharmacogenomics?
Bill: So, people, as you can imagine, do get quite irate about this sort of thing, and there are lots of people that would contest that there is a really big important difference. I suppose that pharmacogenetics is more when you’re looking at single changes in a relatively small number of genes, whereas pharmacogenomics is a broader definition, which can involve looking at the whole genome, lots of genes, and also whether those genes are switched on or switched off, so the expression levels of those genes as well would encompass pharmacogenomics. But ultimately it’s using genetic information to make drug prescription safer and more effective.
Vivienne: So, we’re going to call it pharmacogenomics and we’re talking about everything, that’s it, we’ll go for it. So Matt, just explain if you would the link between pharmacogenomics and personalised medicine. And I know that you’ve done a big Genomics 101 episode about personalised medicine, but just very briefly, what’s the link between the two?
Matt: So, personalised medicine’s about using the right dose of the right drug for the right individual. And so pharmacogenomics helps you with not only ensuring that you give a medication which doesn’t cause problems for the person who receives it, so an adverse drug reaction, but also that they’re actually getting the right dose. Of course, people’s ability to metabolise, activate and respond to drugs genetically is often genetically determined, and so sometimes you need to adjust the dose up or down according to a person’s genetic background.
Vivienne: Now, one of the things that we’ve become very aware of is adverse drug reactions, and I think they account for something like six and a half percent of all hospital admissions in the UK, so it’s absolutely huge. Is that genetically determined adverse drug reactions?
Matt: So, the answer to that is we believe so. There’s quite a bit of data to show that you can reduce the risk of people needing a hospital admission by screening genetic markers, and a lot of the very severe reactions that lead to people being admitted to hospital are very strongly genetically determined. So for example, there are HLA types that affect the risk of adverse drug reactions to commonly used medications for gout, for epilepsy, some HIV medications and so on, where in many health services around the world, including in England, there are already tests available to help prevent those leading to severe reactions. It’s likely though that actually the tests we have available only represent a small fraction of the total preventable adverse drug reactions were we to have a formal pre-emptive pharmacogenomics screening programme.
Vivienne: Now, I should say that not all adverse drug reactions are genetic in origin. I mean, I remember a rather nasty incident on the night when I got my exam results for my finals, and I’d actually had a big bee sting and I’d been prescribed antihistamines, and I went out and I drank rather a lot to celebrate, and oh my goodness me, I was rather ill [laughter]. So, you know, not all adverse drug reactions are genetic in origin. There are other things that interact as well, just to make that clear to people.
Matt: Yes, I think that’s more an interaction than an adverse drug reaction. In fact frankly, the most common adverse drug reaction in hospitals is probably through excess amounts of water, and that’s not medically determined, that’s the prescription.
Vivienne: Let me now come to Anita. So, you talk to patients all the time about pharmacogenomics in your role. You’ve been very much involved in patient and public involvement groups at the Wolfson Centre for Personalised Medicine in Liverpool. What do patients think about pharmacogenomics? Is it something they welcome?
Anita: I think they do welcome pharmacogenomics, especially so with some of the patients who’ve experienced some of the more serious, life threatening reactions. And so one of our patients has been doing some work with the Academy of Medical Sciences, and she presented to the Sir Colin Dollery lecture in 2022, and she shared her story of having an adverse drug reaction and the importance of pharmacogenomics, and the impact that pharmacogenomics can have on patient care.
Vivienne: Now, I think that was Stevens-Johnson syndrome. We’re going to hear in a moment from somebody who did experience Stevens-Johnson’s, but just tell us briefly what that is.
Anita: Stevens-Johnson syndrome is a potentially life threatening reaction that can be caused by a viral infection, but is more commonly caused by a medicine. There are certain groups of medicines that can cause this reaction, such as antibiotics or anticonvulsants, nonsteroidal anti-inflammatories, and also a drug called allopurinol, which is used to treat gout. Patients have really serious side effects to this condition, and they’re often left with long-term health complications. The morbidity and mortality is considerable as well, and patients often spend a lot of time in hospital and take a long time to recover.
Vivienne: And let’s now hear from Jane Burns for someone with lived experience of that Stevens-Johnson syndrome. When Jane Burns was 19, the medicine she took for her epilepsy was changed.
Jane: I remember waking up and feeling really hot, and I was hallucinating, so I was taken to the Royal Liverpool Hospital emergency department by my parents. When I reached A&E, I had a temperature of 40 degrees Celsius. I was given Piriton and paracetamol, and the dermatologist was contacted. My mum had taken my medication to hospital and explained the changeover process with my epilepsy medication. A decision was made to discontinue the Tegretol and I was kept in for observation. Quite rapidly, the rash was changing. Blisters were forming all over my body, my mouth was sore and my jaw ached. My temperature remained very high. It was at this point that Stevens-Johnson syndrome, or SJS, was diagnosed.
Over the next few days, my condition deteriorated rapidly. The rash became deeper in colour. Some of the blisters had burst, but some got larger. I developed ulcers on my mouth and it was extremely painful. I started to lose my hair and my fingernails. As I had now lost 65 percent of my skin, a diagnosis of toxic epidermal necrolysis, or TEN, was made. Survivors of SJS TEN often suffer with long-term visible physical complications, but it is important to also be aware of the psychological effects, with some patients experiencing post-traumatic stress disorder. It’s only as I get older that I realise how extremely lucky I am to have survived. Due to medical and nursing expertise, and the research being conducted at the time, my SJS was diagnosed quickly and the medication stopped. This undoubtedly saved my life.
Vivienne: Now, you’ve been looking at the development of a passport in collaborating with the AMS and the MHRA. Tell me a bit more about that.
Anita: Yes, we set up a patient group at the Wolfson Centre for Personalised Medicine approximately 12 years ago, and Professor Sir Munir Pirmohamed and I, we wanted to explore a little bit more about what was important to patients, really to complement all the scientific and clinical research activity within pharmacogenomics. And patients recognised that, alongside the pharmacogenomic testing, they recognised healthcare professionals didn’t really have an awareness of such serious reactions like Stevens-Johnson syndrome, and so they said they would benefit from having a My SJS Passport, which is a booklet that can summarise all of the important information about their care post-discharge, and this can then be used to coordinate and manage their long-term healthcare problems post-discharge and beyond. And so this was designed by survivors for survivors, and it was then evaluated as part of my PhD, and the findings from the work suggest that the passport is like the patient’s voice, and it really does kind of validate their diagnosis and raises awareness of SJS amongst healthcare professionals. So, really excellent findings from the research, and the patients think it's a wonderful benefit to them.
Vivienne: So, it’s a bit like a kind of paper version of the bracelet that you sometimes see people wearing that are on steroids, for instance.
Anita: It is like that, and it’s wonderful because it’s a handheld source of valuable information that they can share with healthcare professionals. And this is particularly important if they’re admitted in an emergency and they can’t speak for themselves. And so the passport has all that valuable information, so that patients aren’t prescribed that drug again, so it prevents them experiencing a serious adverse drug reaction again.
Vivienne: So, Stevens-Johnson, Bill, is a really scary side effect, but what about the day to day benefits of pharmacogenomics for patients?
Bill: So, what we’ve seen is that the limited adoption so far in the UK and other countries has focused particularly on severe adverse drug reactions. They’ve been easier to identify and there’s a clear relationship between some drugs and some genetic changes where that information is useful. So a good example has been the recent adoption of pharmacogenetic testing for a gene called DPYD for patients undergoing cancer treatment, particularly breast and bowel cancer. And if you have an absence of the enzyme that that gene makes, if you’re given that treatment, then you can end up on intensive care and die, so it’s a really significant side effect. But as you say, the most common side effects aren’t necessarily fatal, but they can have a huge impact upon people and on their wellbeing.
And it’s not just in terms of side effects. It’s in terms of the effectiveness of the medicine. Because if a person is prescribed a medicine that doesn’t or isn’t going to work for them then it can take them longer to recover, to get onto the right medicine. That can have all sorts of detrimental effects. And so when we’re thinking about introducing pharmacogenetics more broadly rather than just on a single drug or a single gene basis, we’re thinking about that for common drugs like antidepressants, painkillers, statins, the drugs that GPs are often prescribing on a regular basis to a whole range of patients.
Vivienne: So, to go back to you, Anita, we’re really talking about dose here, aren’t we, whether you need twice the dose or half the dose depending on how quickly your body metabolises that particular medicine. How do patients view that?
Anita: Well, the patient in question who presented for the Academy of Medical Sciences, I mean, her take on this was, she thinks pharmacogenetics is wonderful because it will allow doctors and nurses to then prescribe the right drug, but also to adapt the dose accordingly to make sure that they get the best outcome, which provides the maximum benefit while also minimising any potential harm. And so from her perspective, that was one of the real benefits of pharmacogenomics. But she also highlighted about the benefits for future generations, the fear of her son taking the same medicine and experiencing the same reaction. And so I think her concerns were, if we have pharmacogenetic testing for a panel of medicines, as Bill mentioned then, then perhaps this would be fantastic for our children as they grow up, and we can identify and predict and prevent these type of reactions happening to future generations.
Vivienne: And some of these drugs, Bill, are really very common indeed, something like codeine. Just tell us about codeine, ‘cos it’s something – whenever I tell this to friends [laughter], they’re always completely entranced by the idea that some people don’t need nearly as much codeine as others.
Bill: Yeah, so codeine is a drug that’s very commonly used as a painkiller. To have its real effect, it needs to be converted in the body to a different drug called morphine, and that is done by an enzyme which is made by a gene called CYP2D6. And we all carry changes in CYP2D6, and the frequency of those variants, whether they make the gene work too much or whether they make it work too little, they vary enormously across the world, so that if you go to parts of Africa, about 30 percent of the population will make more of the CYP2D6, and so they will convert the codeine much more quickly, whereas if you go to the UK, maybe up to ten percent of the white population in the UK just won’t be converting codeine to morphine at all, so they won’t get any benefit from the drug. So at both ends, you have some people that don’t respond and some people that respond a little bit too much so that they need either an alternative drug or they need a different dose.
Vivienne: So, all those people who say, you know, “My headache hasn’t been touched by this painkiller,” and we say, “What a wimp you’re being,” actually, it’s to do with genetics.
Bill: Yeah, absolutely. There’s a biological reason why people don’t – not for everybody, but for a significant number of people, that’s absolutely right, and we can be far more tailored in how we prescribe medication, and get people onto painkillers that work for them much more quickly.
Vivienne: And that’s so interesting that it varies by where you come from in the world, because that means we need to give particular attention – and I’m thinking, Anita, to working with patients from different community groups, to make sure that they understand the need for pharmacogenomics.
Anita: I think that’s really important, Vivienne, and I think we are now having discussions with the likes of Canada SJS awareness group, and also people have been in touch with me from South Africa because people have requested the passport now to be used in different countries, because they think it’s a wonderful tool, and it’s about raising awareness of pharmacogenomics and the potential benefits of that, and being able to share the tools that we’ve got to help patients once they’ve experienced a serious reaction.
Vivienne: So, pharmacogenomics clearly is important in the prevention of adverse drug reactions, better and more accurate prescribing, reduced medicines wastage. Does this mean that it’s also going to save money, Bill, for the NHS?
Bill: Potentially. It should do if it’s applied properly, but there’s lots of work to make sure that not only are we using the right evidence and using the right types of tests in the laboratory, but we’re getting the information to prescribers, so to GPs, to pharmacists, to hospital doctors, in a way that is understandable and meaningful, such that they can then act upon that information. So, the money will only be saved and then can be reused for healthcare if the whole process and the whole pathway works, and that information is used effectively.
Vivienne: So, a lot of research to make sure that all of that is in place, and to demonstrate the potential cost savings.
Bill: Yes. I mean, there are very nice studies that have been done already in parts of the world that have shown that the savings that could be accrued for applying pharmacogenetics across common conditions like depression, like in patients to prevent secondary types of strokes, are enormous. They run into hundreds of millions of pounds or dollars. But there is an initial investment that is required to make sure that we have the testing in place, that we have the digital pathways to move the information in place, and that there’s the education and training, so that health professionals know how to use the information. But the potential is absolutely enormous.
Vivienne: Matt, can I turn now to the yellow card. So, people will be very familiar with the yellow card system. So, if you have an adverse reaction, you can send a yellow card in – I mean, literally, it is a yellow card [laughter]. It does exactly what it says on the tin. You send a yellow card to the MHRA, and they note if there’s been an adverse effect of a particular medicine. But Genomics England is teaming up with the MHRA to do something more with yellow cards, and we’re also doing this with the Yellow Card Biobank. Tell us a bit more.
Matt: So, yellow card’s a great scheme that was set up decades ago, initially starting off, as you said, with literally yellow cards, but now actually most submissions actually come online. And it’s important to note that submissions can come not just from healthcare providers, but majority of submissions actually come from patients themselves, and that people should feel free, if they feel they’ve had an adverse drug reaction, to report that themselves rather than necessarily depending on a medical practitioner or the healthcare provider to create that report. So, Genomics England is partnering with the MHRA in building what’s called the Yellow Card Biobank, the goal of which is to identify genetic markers for adverse drug reactions earlier than has occurred in the past, so that we can then introduce genetic tests to prevent these adverse drug reactions much sooner than has occurred previously.
So, what we’re doing is basically at the moment we’re doing a pilot, but the ultimate plan is that in future, patients who report a serious adverse drug reaction through the Yellow Card Biobank will be asked to provide a sample, a blood sample, that we then screen. We do a whole genome sequence on it, and then combine these with patients who’ve had like adverse drug reactions and identify genetic markers for that adverse drug reaction medication earlier, that can then be introduced into clinical practice earlier. And this should reduce by decades the amount of time between when adverse drug reactions first start occurring with medications and us then being able to translate that into a preventative mechanism.
Vivienne: And will that scheme discover, do you think, new interactions that you didn’t know about before? Or do you expect it to turn up what you already know about?
Matt: No, I really think there’s a lot of discovery that is yet to happen here. In particular, even for drugs that we know cause adverse drug reactions, mostly they’ve only been studied in people of European ancestry and often in East Asian ancestry, but in many other ancestries that are really important in the global population and in the UK population, like African ancestry and South Asian ancestries, we have very little data. And even within Africa, which is an area which is genetically diverse as the rest of the world put together, we really don’t know what different ethnicities within Africa, actually what their genetic background is with regard to adverse drug reactions.
The other thing I’d say is that there are a lot of new medications which have simply not been studied well enough. And lastly, that at the moment people are focused on adverse drug reactions being due to single genetic variants, when we know from the model of most human diseases that most human diseases are actually caused by combinations of genetic variants interacting with one another, so-called common disease type genetics, and that probably is similarly important with regard to pharmacogenomics as it is to overall human diseases. That is, it’s far more common that these are actually due to common variants interacting with one another rather than the rare variants that we’ve been studying to date.
Vivienne: So, it’s a kind of cocktail effect, if you like. You know, you need lots of genes working together and that will produce a reaction that you may not have expected if you’d looked at a single gene alone.
Matt: That’s absolutely correct, and there’s an increasing amount of evidence to show that that is the case with medications, but it’s really very early days for research in that field. And the Yellow Card Biobank will be one of many approaches that will discover these genetic variants in years to come.
Vivienne: Now, Matt’s a research scientist. Bill, you’re on the frontline in the NHS. How quickly can this sort of finding be translated into care for people in the NHS?
Bill: So, really quickly is the simple answer to that, Viv. If we look at examples from a number of years ago, there’s a drug called azathioprine that Matt has used lots in some of his patients. In rheumatology, it’s used for patients with inflammatory bowel disease. And the first studies that showed that there was a gene that was relevant to having bad reactions to that drug came out in the 1980s, but it wasn’t until well into this century, so probably 30-plus years later that we were routinely using that test in clinical medicine. So, there was an enormous lot of hesitancy about adopting that type of testing, and a bit of uncertainty. If you move forward to work that our colleague Munir Pirmohamed in Liverpool has done with colleagues in Australia like Simon Mallal around HIV medicine, there was this discovery that a drug called abacavir, that if you carried a particular genetic change, that you had a much higher risk of having a really severe reaction to that. The adoption from the initial discovery to routine, worldwide testing happened within four years.
So, already we’ve seen a significant change in the appetite to move quickly to adopt this type of testing, and I see certainly within the NHS and within other health systems around the world, a real desire to adopt pharmacogenetics into routine clinical practice quickly and at scale, but also as part of a broader package of care, which doesn’t just solely focus on genetics, but thinks about all the other parts that are important in how we respond to medication. So, making sure we’re not on unusual combinations of drugs, or that we’re taking our medicine at the right time and with food or not with food, and all of those other things that are really important. And if you link that to the pharmacogenetics, we’re going to have a much safer, more effective medicines world.
Vivienne: I think one of the joys of working at Genomics England is that you see some of this work really going into clinical practice very fast indeed. And I should say actually that the Wolfson Centre for Personalised Medicine, the PPI group that Anita looks after so well, they’ve been very important in recruiting people to Yellow Card Biobank. And if anyone’s listening to this, Matt, and wants to be part of this, how do they get involved? Or is it simply through the yellow card?
Matt: So at the moment, the Yellow Card Biobank is focusing on alopurinol.
Vivienne: So, that’s a medicine you take for gout.
Matt: Which I use a lot in my rheumatology clinical practice. And direct acting oral anticoagulants, DOACs, which are used for vascular disease therapies and haemorrhage as a result of that. So, the contact details are available through the MHRA website, but I think more importantly, it’s just that people be aware of the yellow card system itself, and that if they do experience adverse drug reactions, that they do actually complete a report form, ‘cos I think still actually a lot of adverse drug reactions go unreported.
Vivienne: I’m forgetting of course that we see Matt all the time in the Genomics England office and we don’t think that he has any other home [laughter] than Genomics England, but of course he still sees some patients in rheumatology clinic. So, I want to now look to the future. I mean, I’m, as you both know, a huge enthusiast for pharmacogenomics, ‘cos it’s the thing that actually, when you talk to patients or just the general public, they just get it straight away. They can’t think why, if you knew about pharmacogenomics, why you wouldn’t want to do it. But it’s not necessarily an easy thing to do. How can we move in the future, Bill, to a more proactive approach for pharmacogenomics testing? Where would we start?
Bill: Yes, so I think we’ve built up really good confidence that pharmacogenetics is a good thing to be doing. Currently, we’re doing that predominantly at the point when a patient needs a particular medicine. That’s the time that you would think about doing a genetic test. And previously, that genetic test would only be relevant for that specific drug. I think we’re moving to a place where, rather than just doing that one test that might be relevant to one drug, we’d be able to do a test which at the same price would generate information that could be relevant at further points in your life if you were requiring different types of medicine. So, that information would then be available in your hospital record, in your GP record, that you could have access to it yourself. And then I think ultimately what we would really love to get to a point is where everybody across the whole population just has that information to hand when it’s required, so that they’re not waiting for the results of a genetic test, it’s immediately within their healthcare record. That’s what we’d call pre-emptive pharmacogenetic testing, and I think that’s the golden land that we want to reach.
Vivienne: So for instance, I might have it on my NHS app, and when I go to a doctor and they prescribe something, I show my app to the GP, or something pops up on the GP’s screen, or maybe it’s something that pops up on the pharmacist’s screen.
Bill: I think that’s right. I think that’s what we’re looking to get to that point. We know that colleagues in the Netherlands have made some great progress at developing pathways around that. There’s a lot of public support for that. And pharmacists are very engaged in that. In the UK, the pharmacists, over the last few years, have really taken a very active role to really push forward this area of medicine, and this should be seen as something that is relevant to all people, and all health professionals should be engaged with it.
Vivienne: And on a scale of one to ten, how difficult is it going to be to implement in the NHS?
Bill: So, that’s a difficult question. I think the first thing is identifying what the challenges are. So I have not given you a number, I’ve turned into a politician, not answered the question. So, I think what has happened over the last few years, and some of our work within the NHS Network of Excellence in pharmacogenetics and some of the other programmes of work that have been going on, is a really good, honest look at what it is we need to do to try to achieve pharmacogenetics implementation and routine use. I don’t think the challenge is going to be predominantly in the laboratory. I think we’ve got phenomenal laboratories. I think we’ve got great people doing great genetic testing. I think the biggest challenges are going to be about how you present the data, and that data is accessible. And then ensuring that health professionals really feel that this is information that isn’t getting in the way of their clinical practice, but really making a difference and enhancing it, and of benefit both to the healthcare system but more importantly to the patients.
Vivienne: Now, when I hear you both talk, my mind turns to drug discovery and research, and Matt, I’m quite sure that that’s right at the top of your mind. Tell us how pharmacogenomics can help in drug discovery and research.
Matt: So, pharmacogenomics, I think actually just genetic profiling of diseases in itself just to start off with is actually a really good way of identifying new potential therapeutic targets, and also from derisking drug development programmes by highlighting likely adverse drug reactions of medications that are being considered for therapeutic trials, or targets that are being considered for therapeutic development. Pharmacogenomics beyond that is actually largely about – well, it enables drug development programmes by enabling you to target people who are more likely to respond, and avoid people who are more likely to have adverse drug reactions. And so that therapeutic index of the balance between likely efficacy versus likely toxicity, genetics can really play into that and enable medications to be used where otherwise they might have failed.
This is most apparent I think in the cancer world. A classic example there, for example, is the development of a class of medications called EGFR inhibitors, which were developed for lung cancer, and in the initial cancer trials, actually were demonstrated to be ineffective, until people trialled them in East Asia and found that they were effective, and that that turns out to be because the type of cancers that respond to them are those that have mutations in the EGFR gene, and that that’s common in East Asians. We now know that, wherever you are in the world, whether you’re East Asian or European or whatever, if you have a lung adenocarcinoma with an EGFR mutation, you’re very likely to respond to these medications. And so that pharmacogenomic discovery basically rescued a class of medication which is now probably the most widely used medication for lung adenocarcinomas, so a huge beneficial effect. And that example is repeated across multiple different cancer types, cancer medication types, and I’m sure in other fields we’ll see that with expansive new medications coming in for molecularly targeted therapies in particular.
Vivienne: So, smaller and more effective trials rather than larger trials that perhaps seem not to work but actually haven’t been tailored enough to the patients that are most likely to benefit.
Matt: Yeah, well, particularly now that drug development programmes tend to be very targeted at specific genetic targets, pharmacogenetics is much more likely to play a role in identifying patients who are going to respond to those medications. So, I think many people in the drug development world would like to see that, for any significant drug development programme, there’s a proper associated pharmacogenomic programme to come up with molecular markers predicting a response.
Vivienne: We’re going to wrap up there. Thank you so much to our guests, Bill Newman, Anita Hanson, Matt Brown, and our patient Jane Burns. Thank you so much for joining us today to discuss pharmacogenomics in personalised medicine, and the benefits, the challenges and the future prospects for integrating pharmacogenomics into healthcare systems. And if you’d like to hear more podcasts like this, please subscribe to Behind the Genes. It’s on your favourite podcast app. Thank you so much for listening. I’ve been your host, Vivienne Parry. This podcast was edited by Bill Griffin at Ventoux Digital and produced by the wonderful Naimah. Bye for now.
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Sarah Crawford: But I would also say it’s okay to grieve the child that you didn’t have that you thought you were going to have. I just think that’s so important. And I think for me, the most difficult thing in the early couple of years was feeling like I couldn’t do that because nobody appreciated that I’d actually lost anything.
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Naimah: My name is Naimah Callachand and I’m head of product engagement and growth at Genomics England. On today’s episode, I’m 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 Joey’s 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 today’s episode, we’d 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 she’s like.
Shaun Pye: Yes. So, the medical stuff is that she’s got DYRK1A syndrome, which was diagnosed a few years ago, which means that she’s 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, let’s throw that in. She’s 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 that’s the medical thing. What’s she like, she’s 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: She’s very strong willed, you know. Once she knows she wants something, it’s impossible to shift her, isn’t it? So, she’s got a lot of self-determination [laughter].
Shaun Pye: So, her obsession at the minute, or it’s fading slightly, which is quite funny, is that she’s become obsessed by – there’s a toy called a Whoozit that she loves, but she became obsessed by the idea of – she was typing buggy baby Whoozit into her iPad, so that’s how she communicates. She’s 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, “It’s not yours,” that drove her insane with excitement, at the idea that she could steal another child’s toy. So, it’s a good example of her because it’s funny, and, you know, it is funny, and she’s so cheeky about it and she flaps her hands, she’s 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 – again, it’s funny when it happens, but you get to the green and she doesn’t even look for the buggies anymore. So, that’s an example.
But she’s a lot of different things, you know, and I suppose the thing that is dawning on us at the minute is that she’s 17, she’s going to be 18 very soon, and, you know, the list of presents that she gets on her birthday is always the same, ‘cos she’s autistic. So, at Christmas, she always gets the same presents. But the idea that, for her 18th birthday, we’re going to have to buy her children’s toys and – you know –
Sarah Crawford: Toddlers’ toys.
Shaun Pye: Toddlers’ toys and everything, it’s sort of hitting home, but that’s something – a bridge we’re going to cross on July 27th [laughter].
Naimah: Yeah, I can imagine that’s quite a difficult bridge to cross, but it sounds like, you know, Joey’s 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 Joey’s been diagnosed with DYRK1A syndrome, but can you tell me what it was like before you both – 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 wasn’t 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 wouldn’t 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 weren’t 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, I’m a clinical psychologist, I’ve 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 wasn’t 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, “There’s nothing wrong with her,” kind of mantra.
Shaun Pye: She wasn’t our first child, so we had experience – and all children are different, but because we had that comparison – all children are different. Obviously, there’s 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 he’d hit, and something wasn’t right. And the parental thing – basically, we’re talking about grandparents – it was sort of – there were two approaches that they took, one of which was to tell us nothing was wrong, because they couldn’t bear the idea that me and Sarah were in pain or unhappy. It was just out of pure love. It’s just a natural human reaction to say, “I’m sure everything’s going to be alright.” They were just trying to be supportive because that’s, 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, “They 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.” And the way I describe it nowadays is that they’d mistaken Joey for someone on the far end of a spectrum of abilities or behaviours, whereas she wasn’t really on that spectrum at all. She was on a different spectrum [laughter]. She wasn’t a difficult child. She wasn’t a naughty child, was she?
Sarah Crawford: No, no, she was a child whose brain hadn’t 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 didn’t take any interest [laughter].
Sarah Crawford: No, it’s more that they ran out of technology, so they couldn’t pinpoint the diagnosis with the technology they had. I mean, the geneticist was excellent, wasn’t he? We really loved him.
Shaun Pye: Yeah, Sarah’s going to like this, ‘cos I’m about to say I love geneticists ‘cos they’re – on the spectrum of doctors, I love them, ‘cos 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 – and in a way, you could have walked away from that thinking, “We wanted the bedside manner and we wanted the, “Oh, that’s terrible,”” whereas he really was just a sort of – 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, ‘cos we’re the same [laughter]. There’s not a Sudoku or a crossword that we don’t love finishing. So, we walked away thinking, “These are exactly the people we want involved.”
And so when I say they gave up, that’s not fair. They just ran out of – you know, they can’t spend increasing amounts of NHS money. So, they tried – 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 – I don’t know if that’s the terminology they would use now – 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 wouldn’t pinpoint in, but that the technology was changing all the time, and that if they didn’t 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 – having said that, I got slightly – but you didn’t – about one of the geneticists, who sat there and said, “We’ll do this test and this test, and if they come back with any interesting things then we can get really excited.” And he used the word excited, and I was sort of a bit, “I’m not that excited by all of this.” But actually I calmed down quite quickly, and in hindsight I really wanted someone to get excited by the idea of working out – but then a long time went past. I wouldn’t say that we lost interest in finding out what her genetic condition was, we didn’t. It’s just it’s something that became less and less – it wasn’t 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, “We’ve got a few more theories,” or something, and she just said, “We’ve found out what it is.” And that moment is – well, we tried to describe it in the TV programme, but it’s quite hard to describe what goes through your mind when, after 13 and a half years, somebody suddenly says, “Oh, by the way, that thing that happened with your daughter, we’ve worked out what it is.”
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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, wasn’t it? I was a bit more excited, Sarah was a bit more…
Sarah Crawford: My attitude early on was that, while the label would be nice to have, it wouldn’t make any material difference to anything to do – I mean, it was never going to be precise enough that it would give a map out of what we’d expect for her as an individual, and it wasn’t going to change the fact that there was a severe learning disability. It wasn’t 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 doesn’t 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. That’s the main takeaway from getting the diagnosis. ‘Cos Unique is great, and obviously in a broad sense it’s great, but to actually meet people and be in touch with people whose children have DRYK1A – so, I’ve met quite a lot of them now and I’ve met quite a few of the children. There was a meetup last year, and you just walk in and you just go, “Oh my god, oh my god” [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 – who’d only, you know, very young, been diagnosed. But just to see your life just in front of you [laughter] is very useful. So, that’s 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 – well, every family from Unique that I’ve ever encountered actually. Nearly all of the DYRK1A – ‘cos it’s spread around the world as well, so, you know, there’s slight cultural differences, but just to see that they are all of a very similar mindset is comforting, ‘cos it sort of makes you think, “Actually, we haven’t been doing this wrong.” It’s a sense of humour thing. It’s an attitude to the world. It’s the way they see their children. It’s the way they see the outside world. I’m not saying we’re all uniform, of course we’re 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 it’s sort of quite reassuring really that, you know, we’re 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 Shaun’s done such a good job of summing up why Unique exists already, thank you, Shaun. But I think really what we’re 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 that’s 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 – that their child isn’t 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, “No, they’re just a bit delayed, it will all be fine.” And so I think that’s a common experience of many families, that the parents inherently understand and know their child better than everyone else, and it’s 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 isn’t 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 who’ve got the same condition, but it might also be families who are just going through the same experiences as you are, so you’ve 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 they’ve been offered, and a bit about the results of genetic testing. Because of course genetics is something that lots of people haven’t thought about since school, and actually quite often hoped they never had to think about again.
Although we’re a group supporting families and patients, actually a big part of what we’re doing is around translating those complicated genetics terms, and trying to explain them to families, so they can understand the testing they’ve 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 doesn’t give you a magic treatment that’s going to cure your child. It’s really important, for all the reasons Shaun and Sarah have already said, just knowing why it’s happened, being able to connect with others, being able to meet others, but actually often it doesn’t necessarily change treatment.
Shaun Pye: I guess one thing I would say, just ‘cos it was important to us, and it’s de novo in our case, but that’s comforting to know. We always suspected it was and we were always told it was, but to have that confirmed means – I mean, we’re not going to have anymore children, but it’s more to do with our son and whether there’s 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: It’s so important to me in hindsight the diagnosis, just for all the reasons that we’ve been discussing, but without doing down the role of genetics, there was a period of Joey’s life when we thought we’d run out of road with the testing, and it wasn’t something that really I was obsessed with or occupied my mind massively. It wasn’t like me and Sarah were saying, “We 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.” We’d sort of resigned ourselves to the fact that they’d done all that they could and they hadn’t found it, and that’s 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, ‘cos I think we’d 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 they’re using obviously was changing all the time, but it didn’t preoccupy me because I didn’t 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 I’m 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. It’s not like anyone was saying, “Oh, with this treatment or that treatment…” Once you know that it’s DYRK1A, there’s 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, we’re not queuing up for experimental stem cell treatment [laughter] in weird and wonderful parts of the world, you know. What’s happened has happened. Her brain didn’t 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, that’s 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 – Joey will never be better, but talking to the other families – eating disorder, that’s one of them. Constipation, that’s another thing. But hearing their experiences, hearing the roads they’ve gone down, finding out that there’s, you know, a unit somewhere in the country that specialises in this, that or the other, these are concrete things. It’s not just about emotional support. It’s absolutely about practical support. But there’s no magic wand, but there are things that, you know, we’ve 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 they’ve received a diagnosis, or are they likely to come quite quickly to you? What’s your experience?
Sarah Wynn: It’s a really good question, and of course we don’t 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 it’s not too daunting. ‘Cos 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 that’s when they’re looking for more information. Actually, you can get in touch with Unique and if you decided you didn’t want to join us, that’s also fine. So, we have a helpline that you can call. And for some people, joining a support group just isn’t their cup of tea, and that’s really fine. Other people find us a little bit later on, you know, perhaps when their child starts school or, you know, there’s 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 we’re there. So, that’s a really important thing for us is that everybody knows we’re there. You can join us and involve yourself as much or as little as you want. So, as we’ve 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 you’d 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 don’t want to go to the meetups, or they’re not quite ready to do that. And of course people change. So, some people join us and think, “We’re just going to quietly sit here for a bit,” 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 people’s 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. That’s not an ideal that they aspire to. That’s what it’s like. So, I can confirm that – I mean, people think different things, and within our DYRK1A group, for example, you know, there’s a broad range of people who think various things, but the one thing about it and Unique is it’s very well self-policed, so people know how to behave. You won’t be subjected to ill informed sort of medical nonsense. It’s very well self-policed, but it’s also very, very occasionally – I’m speaking for the DYRK1A group – the example they gave me was around covid and vaccinations, and, you know, people have very strong views about it, and these forums aren’t the places to be having that sort of discussion.
Sarah Wynn: I think that’s 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 it’s their safe space. But yeah, ever so occasionally, it needs just a tiny little bit of input. But yeah, I think Shaun’s right, everybody’s there for the same reason, and that’s 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 it’s 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. Let’s listen to the poignant clip from the series by Jessica Hynes, who plays the mother, Emily.
Emily: You know, when you’re younger and daydream about what family you might have – 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 wasn’t the girl that I dreamt about, you know. She’d taken her place. And then as she got older and I accepted her more, you know, what if it wasn’t that she’d 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 wouldn’t have to… I wouldn’t have to resent Rosie anymore because I’d have the family that I’d always wanted, and I’d have – I’d have Rosie as well, yeah. [Sobbing] Just after all these years, haven’t 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 it’s meant in the aftermath as well.
Shaun Pye: So, it came about - I basically am a TV writer and Sarah’s a psychologist, but it came about primarily because I was trying to think of something to write about and we realised that Joey’s just an incredible character. Those sort of children aren’t 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, “You’re not doing that, it’s not honest enough” [laughter]. So, Sarah came on board as a writer with me and we cowrote it. The whole thing’s cowritten. And it’s the most important piece of work I’ve 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, “It’s like looking at our own lives on television,” it was recognition. It was nothing to do with whether the stupid jokes were funny or anything [laughter]. It was purely whether – if anyone had turned round and said, “This has got nothing to do with what it’s like bringing up our child,” or our brother or sister or whatever, that would have been quite bad for us, but it wasn’t, and that’s been the overwhelming response since. It’s, “Thank you for putting our life on television, ‘cos it’s not normally on television.”
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 isn’t 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. Joey’s 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 ‘cos that was such an important part of what we’d 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 that’s what it became.
Naimah: I’m 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 it’s 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 it’s 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 – 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 wasn’t always the most comfortable process, you know. We’d sort of agree – I mean, particularly in the earlier process, we’d sort of have a little think about what we wanted to talk about, and then I’d go off and like kind of delve deep into memory, and just type a stream of consciousness, and I’d 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 – yeah, strange how things evolve.
Shaun Pye: Yeah, I think possibly if we hadn’t done this then we might have just tried to not think about these things and not bring them back, and I think we probably wouldn’t have spoken to each other – we may have, I don’t know. I don’t know what would have happened. But I don’t 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 – out of love again, there’s 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, “Well, I didn’t say that there was nothing wrong with her,” and, “I didn’t say this or that,” 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 it’s all good.
Sarah Crawford: I think there’s something about seeing it, you know, and especially given, you know, we were so fortunate with the cast because they’re so good at portraying it. And I think there’s 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 it’s really great for other families going through similar circumstances, for their families to see what’s happening and, you know, there’s a lot that can be learned from the programme as well. So, you know, it’s, 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 didn’t do it to represent everybody’s 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 it’s had a hugely positive reaction from our Unique community. And I think it’s not always an easy watch, I think lots of families would say it’s challenging to see it up close in front of you, but I think it’s really cathartic and has been just incredibly powerful at showing these sorts of stories, which, as you said, just don’t get shown very often.
And I think particularly when we think that rare conditions, although they’re individually rare, if you put all of the rare chromosome conditions together, they’re 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, it’s the same with the show. I’ve had lots of people get in touch with me or talk to me in person and say, “I’m really sorry, I tried to watch ‘There She Goes’ and I can’t watch it,” and I have to say, “Don’t apologise, you have nothing to apologise for. You take what you need from it. If you can’t watch it then don’t watch it. If you can watch it then do. There is literally no right or wrong way of doing this. There really isn’t.” But having said that, the nicest comment – well, one of the nicest comments I’ve seen was on the DYRK1A forum. It was someone who casually referred to it as “our show,” as in the DYRK1A community, it belongs to them, and that – 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. That’s really nice.
Sarah Wynn: Also from the Unique and general people who have rare conditions community, it’s been so fantastic for raising awareness about genetic testing and rare conditions in general, and, you know, there just isn’t – because these stories don’t get talked about or shown about very often, it’s 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 programme’s 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, “Our family’s being heard and represented,” which I think is really important. But yes, we’ve 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 who’d been members for a long time but perhaps had been a bit quiet, or hadn’t 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 hadn’t been.
So, it has just been such a brilliant, brilliant experience to have Unique as part of it. And I think that’s really important. At Unique, we have members from 120 different countries, and the reason is that when you have these rare conditions, you’re 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, that’s 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 there’s no right or wrong way of doing this. I would say, from my experience, don’t be hard on yourself, and you’re going to think that you wish it never happened to you and that’s fine. That is absolutely fine. That’s normal. We’ve all thought that. It doesn’t 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, ‘cos 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 we’ve encountered a little bit of, you know, “As long as you love them, that’s the most important thing,” and, you know, which is fine and that is an okay perspective to have, but there are times when it’s just not what you want to hear. I want to be allowed to feel the feelings that I’m having without feeling guilty.
So, I would encourage people to seek support from Unique or from wherever. But, you know, generally, the thing I’ve 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 don’t be harsh on yourself, because, you know, you’re allowed to find it difficult. But I would also say it’s okay to grieve the child that you didn’t have that you thought you were going to have. I just think that’s so important. And I think for me, the most difficult thing in the early couple of years was feeling like I couldn’t do that because nobody appreciated that I’d actually lost anything. The world seems to use the word difference a lot at the minute, you know, “These children are different, they’re differently abled,” but actually it is disability [laughter], and it is more difficult, you know.
There are rewards, there are positives, but, you know, she’s 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 don’t think that should get lost. Because I think parents need to feel it’s okay to get the help they need and to push for the help they need, and not feel like they’ve just got to kind of put on a brave face and, you know, as Shaun was saying, the attitude sometimes of, “Well, you’ve just got to get on with it.” Because while you do, actually, you know, you do need help to do that. It is difficult.
Shaun Pye: The only other thing I’d say is, just ‘cos 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 I’m sure in his mother’s opinion as well, but my experience, never forget about the toll it takes on siblings. ‘Cos Frank is a very, very loving brother. Only last night, Joey was typing, “Frank book.” ‘Cos he’s 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 it’s not really advice, it’s just, you know, there’s a danger that Joey could have taken over our entire family life, and especially Sarah made sure that didn’t happen and that, you know, we were a unit and he was – but, you know, it is possible that it can swallow up your entire life.
[Music]
Naimah: Okay, so we’ll 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 Sarah’s journey to Joey’s diagnosis, and how charities like Unique can support families of those living with rare conditions. If you’d like to hear more like this, please subscribe to the G Word on your favourite podcast app. Thank you for listening. I’ve been your host and producer, Naimah Callachand, and this podcast was edited by Bill Griffin at Ventoux Digital.
So, as this DNA instruction manual is quite long, it needs to be broken up into smaller sections that the body can read, and that’s 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 they’re 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 it’s 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, it’s really tightly packed into our nucleus, and the
region we’re 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 it’ll use the instructions that are encoded by the messenger RNA. But we need materials to build the protein, and that’s 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 it’s eventually exported by the cell to where it’s 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, it’s actually much more stable than RNA, which is more susceptible to degradation by enzymes and other molecules. As DNA contains our genetic code, it’s much longer than RNA, and you can only find DNA in the nucleus of the cell as it’s 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 DNA’s is the T lettering and RNA’s 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. That’s where we get the deoxyribonucleic acid and the ribonucleic acid.
Naimah: So Clare, we’ve 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, it’s 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 you’d like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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 – I don’t 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, “Oh gosh, I haven’t buried all these feelings of hope.” 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 don’t know if it’s been described as like a nail in the coffin experience, because I really hadn’t realised I was still clinging to this hope all that time, and then again it was, you know, another, “No, nothing’s there.
Lisa: My name is Lisa Beaton and I’m a member of the participant panel at Genomics England. On today’s episode, I’m 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 we’ll 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 today’s episode, we’d 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, I’m Celine, I’m 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: I’m Jana Gurasashvili and I’m 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, I’m Louise Fish, I’m 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, it’s clear they have a genetic condition, but science hasn’t 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. It’s brilliant being a part of my big SWAN UK family. We first realised that there were some – I suppose something wrong with our daughter when she was around two weeks of age, but it wasn’t something I could specifically put my finger on. I couldn’t at that point have taken her to a doctor and said, “I don’t know what’s wrong but there’s something wrong.” I just knew in my heart of hearts, probably because I have three elder children, that there were issues, and things weren’t 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 didn’t 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, “She feels wrong.”
And I think that’s quite a SWAN UK experience, from chatting to other families with similar situations. The parents just know that there’s 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 wasn’t 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 wasn’t 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, that’s 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, there’s 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 don’t 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 child’s phenotype or clinical condition. So, that’s what we mean really when we’re 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 don’t have a genetic likelihood cause, just a gene thrown up to diagnose their child?
Louise: Yeah, I think it’s a huge challenge for families, and you’ll 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 that’s going to be on their child and on the child’s life, and on the family’s 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, there’s a real concern on behalf of families, a, that they don’t understand how their child’s going to be affected by the condition. What we’re really careful to say to families is, “Just ‘cos you don’t 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.” But I think that moment of not getting a diagnosis is when people feel I think real – the uncertainty continues, and uncertainty, we know, is a really hard thing to live with, and the lack of clarity about which services you’ll be able to access. So, I think psychologically it’s 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 daughter’s list of various different conditions kind of – 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 there’s 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, “Oh well, that’s great news,” and to some extent it was great news that something hadn’t been found, but also if that hadn’t 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, “Oh well, if they haven’t found anything then there can’t be too much wrong.” 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 doesn’t 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 there’s a tendency to downplay that there is an issue and that perhaps, you know, you’re 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 I’ve 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 hadn’t done anything wrong during their pregnancy to cause the child’s condition, and that’s 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 there’s also a drive from many parents to feel that they’re 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 who’d 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 didn’t do, something I thought of, something I hadn’t 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 don’t 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 – 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 layman’s 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, I’m sure, probably just as much for those of us who don’t have that diagnosis.
Louise: Yeah, just to add to that, I think that’s absolutely right, Lisa, and I just want to give a shoutout – at SWAN UK, we tend to support families who don’t 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 we’re very happy to keep them because of the support they’re 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 you’ve talked about, where people have finally got a diagnosis and it’s that kind of relief of having a name, but it’s a super long name, and you find out you’re one of only three families in the world with that diagnosis. And so although there’s a real I think comfort for people, perhaps if you have a five year old and you’re 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 there’s 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 child’s 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 they’re on, because there’s still a huge amount of uncertainty for families with those super rare conditions, as you say.
Lisa: Definitely, and I’m sure you’ll 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, “Can we still remain part of the SWAN UK family?” 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 that’s very comforting to the members.
Louise: Absolutely, yeah, I think that sense of belonging and being able to reach out to other families that you’ve 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 they’re 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 can’t 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 won’t 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 don’t 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 you’ve 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 it’s clear that, from your work, you’re 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 child’s condition, and that they’d 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 they’d 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 it’s 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, you’ll 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 doesn’t necessarily mean that they won’t get a diagnosis at some point in the future. So, there’s 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 we’re using in whole genome sequencing. So, I don’t 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, I’d gone to so many appointments and thought, “Oh, this’ll be the time that I turn up and somebody will tell me this is what is the diagnosis.” 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 wouldn’t 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 – I don’t 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, “Oh gosh, I haven’t buried all these feelings of hope.” 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 don’t know if it’s been described as like a nail in the coffin experience, because I really hadn’t realised I was still clinging to this hope all that time, and then again it was, you know, another, “No, nothing’s there.”
And I think because of the work I’ve 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 didn’t mean that the study, everything was closed to us. It didn’t mean, you know, that things won’t 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 it’s quite hard to pick yourself up and dust yourself off again, to be like, “Okay, we’re still here, we’re still circling that drain,” 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 there’s hope and there’s realism, and somewhere along the way, if you’ve 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, we’re still hopeful that one day we might get some answers, but we’re 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, that’s our experience. And also I think if I’d 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 you’ve described it really eloquently and better than I’ll 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 tomorrow’s 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 that’s really welcome. So, making sure that people who’ve already had whole genome sequencing but not found anything continue to have access to that potential reanalysis I think is really important.
As you’ve 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 that’s 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 it’s 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 that’s through the genetics team or a particular discipline, perhaps the one that is the closest fit for their child’s 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 don’t have a diagnosis, who’s 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 don’t have a clear diagnosis, who’s 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 that’s going to pull that multidisciplinary team together and make sure that your child’s not being prescribed stuff that’s contraindicated, or that’s 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 they’re 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 doesn’t have a clear diagnosis. And so we’re 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, you’ve 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 we’re 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 it’s not contraindicated from a neuromuscular side of things and so forth.
It’s 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 that’s 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 child’s 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, ‘cos they had to keep repeating their story over and over again, particularly ‘cos they didn’t 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, it’s quite a unique experience. You are the specialist for your own child in that sense, I think would be the way I’d describe it. And I suppose over the years, I’ve got so used to sort of trotting out different medical explanations in terms that you can almost sound like you know what you’re doing [laughter]. And a few times when I’ve been at medical appointments, and perhaps we’ve met a new specialist or consultant, they’ve said, “Oh, what’s your field? What’s your area of expertise?” And actually you just think, “No, I’m just a specialist in my own child” [laughter]. But that’s 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 didn’t 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 didn’t 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 she’s asking her own questions, and our older children are at a stage in life where they’re looking at potentially having families in the future, I know that those things have come up, and we’re 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 child’s condition?
Jana: Yes, well, I’m sorry to hear you didn’t 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. It’s 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 they’d known how many were not getting results. So I think in the longer run, it’s 40 percent perhaps received a result, so that’s 60 percent that didn’t receive a result, so those parents were not alone, but they felt very alone. And some suggested if they’d just had a leaflet really explaining that, and explaining that they’d 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 they’re 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 you’d been able to forget that you’d 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 you’re 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 child’s condition even without a diagnosis, so what’s 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 don’t 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 it’s also really important to add that hope isn’t necessarily lost when you don’t 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, “In light of the new information that we now have from the whole genome sequencing result, what are you hoping for now?” So in a way, it’s 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, it’s sort of somewhat of a Pandora’s box really, isn’t it, in that we’re almost kind of finding the information out quicker than we actually know how to process it and what it potentially means. So actually if there’s a genetic counsellor available to speak to those parents, or for those parents to be signposted to somebody who can say, “Well look, since you were recruited, actually this is happening, that’s happening,” or, “These research projects are happening,” 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 we’ve already touched on, it’s 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. It’s normal. You might also want to explore people, not only what they’re 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 didn’t really want that certainty.
And also helping parents to explore how not receiving a result might feel, so that they’ve actually rehearsed it a little bit, and where they might go to when they need a bit of extra support. So, they already know, “I go and talk to my friends, that’s where I get my support from,” so that they’re kind of ready for it, and that might help them with that sense of isolation, but also validating these feelings. So, it’s okay, it’s okay to have that dip, it’s okay to feel, that it’s 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 they’ve got those to draw on. And as you’ve mentioned, Lisa, it’s like having your own resources also helps generate that feeling of empowerment and control. And as Celine has said, it’s really facilitating parents through that passage of reframing what you’re hoping for, reframing what the future looks like, if you had one picture of a future. You need to become comfortable with the future you’re now looking at.
Lisa: Thank you, Jana. Louise, if I can ask you really, we’ve 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 it’s based on a really strong understanding of what it’s 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, it’s 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. They’re often kind of practical questions about, you know, “My child needs this kind of wheelchair, has anybody been able to source that from somewhere?” “My child’s having real difficulties eating at the moment, can anyone give some advice on this particular challenge?” “This thing someone else has faced, how did you approach it? Where did you reach out for support?” 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 there’s 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 don’t have a diagnosis, and some of it is just trying to have social events and bring people together again. We’ve had, for example, an active dads group in Wales, who’ve 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, that’s kind of the nub of SWAN UK and what we do, and then alongside that, that kind of fits in with Genetic Alliance’s 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 don’t have a diagnosis is better joined up. And that we feel has been a real success. Again, there hasn’t 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 we’re 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 who’ve 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 don’t get an answer. And that won’t 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 don’t yet necessarily know exactly what that reanalysis will look like, and it’s 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, there’s some amazing investment by the UK government in genomic research, and that’s 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 don’t have a diagnosis, and that help for families who don’t 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 they’re 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 isn’t 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 patients’ symptoms, and often a diagnosis doesn’t 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, it’s 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 you’d like to hear more like this then please subscribe to the G Word on your favourite podcast app. Thank you for listening. I’ve been your host, Lisa Beaton. This podcast was edited by Mark Kendrick at Ventoux Digital, and produced by Naimah Callachand.
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 can’t do its job anymore, and could be very significant for that person’s health.
Naimah: And how do we find these gene variants?
Helen: Gene variants are exactly what we’re looking for when we’re 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. We’re finding these through doing genetic testing or genomic testing, so looking at an individual gene, a series of genes, or even across someone’s 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 you’d like to find out some more information on that as well. So, moving on with the next question, how is a variant’s 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 patient’s 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 person’s 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 that’s seen, as to whether that would make sense for that individual. So, it’s a lengthy process but an important one, to make sure that we’ve got the most accurate information about that variant, and the understanding about that in that person’s health and development.
Naimah: So then, what would be a variant of uncertain significance?
Helen: So, the output of that clinical scientist’s work looking at whether a variant is significant or not comes out into five categories, but three main groupings. What we’re 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 don’t make an effect on the gene, that would be benign. We would call those harmless variants, things that don’t change the gene and wouldn’t be expected to be associated with a condition.
And then, in life there’s 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 doesn’t impact the gene and is harmless. We have variants that we find that we do not yet understand, and that’s basically because our knowledge as of when the variant is looked at is good, but it’s not perfect. There could be more to learn about particular variants or particular conditions, but at the moment we just don’t have enough information to be sure one way or the other. And that’s really important, we’ve 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 we’re trying to genetically diagnose patients?
Helen: They are relatively common for us to encounter, and that’s 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 it’s still improving at a rapid rate, but we don’t know everything yet, so there will be areas where we haven’t met a particular variant before, or we can’t predict how it might affect that gene, or there’s some uncertainty about it because we don’t have full knowledge yet. So, it does happen relatively commonly, and it probably happens more commonly the more genes or the more information we’re looking at. So a test looking across someone’s genome, like whole genome sequencing, we’re more likely to come across these things than if we’re 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. It’s 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 don’t 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. It’s really important this is correct.
Naimah: And finally, I just wanted to ask, can we reclassify variants of uncertain significance?
Helen: Yes, there’s 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. It’s 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 don’t have the same rare disorder, so we’re starting to see, well actually, maybe it’s harmless and it’s 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. I’ve been your host, Naimah Callachand, and if you’d like to hear more explainer podcasts like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.
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 I’m your host for today’s 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 we’ll 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 today’s 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, Mila’s, story. My life as a mother started really like anyone else’s, 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 years’ 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 years’ 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 years’ 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 years’ old I brought her into the emergency room in the Children’s 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 daughter’s form of Batten Disease. But that there was a tiny glimmer of hope that we could maybe stop genetic disease, and that’s all I needed. I started Mila’s Miracle Foundation, which is a non-profit organization. I started telling Mila’s 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 didn’t 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 wouldn’t 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 Mila’s genome to figure out where this missing mutation was. And in that search I crossed paths with a Dr Timothy Yu at Boston Children’s 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 Mila’s missing mutation and finally diagnose her fully with this rare form of an already rare Batten disease.
That is where Mila’s story changed and turned direction. At that point, a recently approved drug for spinal muscular atrophy was on all neurologists’ 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, “What if we did the same thing for these children? What if we made a drug like this for Mila?” This drug called Antisense Oligonucleotides, or ASO seemed to be a good fit for Mila’s 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 years’ 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 didn’t know what to expect but I knew that she was going to lose all her abilities and die if she didn’t 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 family’s 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 wasn’t 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 Mila’s 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. I’m a very positive happy person and I have a son and I continue getting up every day and pushing through the day but I’m 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 Mila’s disease and give her a full diagnosis. So once we managed to have Dr Yu’s 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 didn’t 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 don’t know and maybe you’re just a little bit over-worked and over-worried about things, and having no answer and no idea what’s wrong is like living in this limbo that’s 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 it’s true, of knowing what is wrong and then thinking, “What could I do about it now?” And so for me I would say that’s how, Ana Lisa, that’s 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 wasn’t 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, I’m 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, that’s something I think in the UK we’re 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 ‘The 100,000 Genome Project’ 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, we’re 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 it’s one of the things which has really changed the way we can go about this, but we also know that there’s still, it’s 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 it’s 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 it’s about equity of access and I think that mind-set that you bring is so important.
Julia: Yes, Rich, I think it’s a really good point you know, because a lot of parents like myself, we’re 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 that’s already dealing with pain and confusion and not understanding what’s going on, not to mention usually that child, in my case, Mila, is having problems that it’s 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 it’s 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 shouldn’t 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, it’s happened a number of times to me where a physician has said, “Well, you know, there is this rare condition but I’m not going to bring that up because it’s so rare that the likelihood that your daughter has that, I wouldn’t want to scare you.” 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 can’t have the tapping on the knee and stacking up blocks and running down the hall for months and years just to figure out what’s 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 that’s definitely one thing that we’ve 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 we’ve got amazing colleagues working on diagnostic discovery looking at whole cohorts of patients now who are having whole genome sequencing and that’s 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 that’s one of the examples where sort of thinking about making sure that service is available early and rapidly is being set up and that’s been really successful and identifying a cause where that really changes the care of that child on intensive care.
The other area where we’re 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 we’re 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 there’s 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 Lisa’s 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 it’s thinking about how we set ourselves up to make sure that we’re able to take advantage of that to its full.
Julia: Yeah, and I think it’s a great, I’m 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, that’s where we need to be. You know it’s 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 Mila’s 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 they’re diagnosed before they have symptoms and they’re 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 it’s like living with a rare condition, and this is a step in that direction to help.
Effie Parks: Hi there, I’m 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. It’s 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 let’s navigate this path together.
Ana Lisa: Julia, I’m 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 that’s required across the genomics ecosystem to achieve that.
Julia: Yeah, that’s a really good question. It’s been seven years that I’ve been thinking about this kind of individualised medicine concept, you know, as Mila kind of became the pioneer in this field and I’m not a scientist, I’m not a physician, but I’ve learned a lot because I’ve 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 I’ve learned so far is that when you have a genetic condition most genetic conditions are individually rare and unfortunately that doesn’t 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 they’re lucky enough, and I hate to use the word ‘lucky’ but they’re 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 they’re 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 – 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 we’re finding them, especially thanks to Genomics England and others, we’re 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 don’t have anything else. And so I think the genomics community, especially in the UK because it’s so well suited with all the efforts that we’ve 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, it’s 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, that’s where it begins, it begins by identifying patients early enough and getting the data that’s 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: I’ve been really inspired by the conversations and the drive that you, Julia, personally have given to those conversations. And I think what’s really interesting and I think it’s 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 it’s relevant you know, in other settings as well.
I’m really interested in some of the conversations that I’ve 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 it’s 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 we’re 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 that’s going to die no matter what, probably very rapidly and that if they don’t 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 they’re going to die otherwise. And they’re willing to spend money and they’re 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 Mila’s going to die no matter what, no child has ever lived with her form of Batten Disease and she’s 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 that’s 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 Mila’s 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 we’ve already set that precedent, we don’t need to be having this discussion again. We know the risk we’re willing to take for a dying child when there’s no other therapeutic, no other option and they’re 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 that’s treated with an individualised different ASO or different medicine that they don’t 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 it’s accessible.
Rich: Yes, and that’s very much back to Ana Lisa’s point on the link and for diagnostics too on continuing to learn and creating a system that recognises that that’s crucial to offering the best care today but also in the future and being able to make proactive decisions more confidently if you’re a policymaker, knowing that you’ll continue to learn, you don’t have to pretend you know everything today.
Julia: It’s very meaningful for parents. So when parents, children, are diagnosed whether it’s a fatal or life-longing debilitating or difficult disease, if you know that what’s being learned from your child both from just the genomics to the potential treatments that that’s 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 it’s learnings and it’s 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 I’d love to dream that actually this could help many, many different patients, with many, many different types of rare conditions because actually we’ve learnt how to target a little bit more at source, perhaps a particular type of genetic variant, and so a bit like cancer, we’re not thinking about breast cancer, we’re 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 you’ve 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, that’s a great dream, I share that dream. Rich, what is your, you’ve been in this for many years, what’s your dream for the next five, ten years?
Rich: I guess I have, I think there’s two aspects to it. I think there’s two, I think there’s 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 we’re 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 it’s 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, we’ll 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, we’re in a substantially different position and I think, I’ve 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 it’s proven, or there’s a pathway that we all understand about how that can be trialled. And I think we’re at the beginning of that journey and I now feel it’s a responsibility of ours to work through how we can bring the right pieces into place, we can’t 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 it’s 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 child’s 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: That’s so promising to hear that. I don’t 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 it’s a real balance between having that hope ourselves, sharing that hope with other people and not giving false hope and it’s such a balance when right now more than 95% of rare diseases don’t have a treatment and I think that’s such a difficult position to be in right now. And everything we’ve been talking about gives me massive hope for the future and a lot of what we’re pouring our energy and efforts into is both the diagnostics so that we’re not trying to make a puzzle with missing pieces in the dark and that’s 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 that’s effective, whether they’ve got a common condition, a rare condition and that’s our driving ideal.
So I think I’m full of hope and optimism and I hope that it will accelerate, that’s what I really hope, the momentum will build and we’ll get to a certain level of knowledge, we’re learning the processes, we’re learning the evidence, we’re 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 Mila’s 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 it’s 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 that’s the data that’s needed to create the treatment.
Right now you guys are you’re 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, here’s where we’re headed, and if we don’t solve both of those problems then there is no such as access, you know to a better life, so I’m really grateful for the fact that you’ve 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 you’re doing.
Rich: Yeah, well I think we feel we’re 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 it’s 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 you’re taking on are very central, they’re not kind of on the sideline, they seem whenever I’m 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, it’s back to that sort of point from Ana Lisa sort of balancing the hope and expectation, I think we’re 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 it’s 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 wouldn’t place it as a barrier but I would highlight it as a strength that we’ve had and I think we’re hopeful that we’ll continue is that long-term commitment in terms of government and the NHS and I think that’s really powerful in this space to maintain the UK’s 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 it’s 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 can’t even be diagnosed or if you’re diagnosed too late, which is what the reality is in the world of rare conditions right, then you know, then it’s a little bit futile to race to a treatment or even think if that’s 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 ‘hope’ that’s the word that keeps me going and doing what I’m doing because if there isn’t any hope it’s pretty hard to keep fighting, so I’m really glad, thank you both for having hope.
Okay, we’ll 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 you’d like to hear more of this, please subscribe to the G Word on your favourite podcast app. And thank you so much for listening. I’ve been your host, Julia Vitarello. This podcast was edited by Mark Kendrick at Ventoux Digital, and produced by Naimah Callachand.
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 ‘what is The Generation Study’. 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.
Vivienne Parry: Hello and welcome to the G Word.
The Festival of Genomics is the UK’s biggest genomics event, and it’s become an essential part of our year. It’s free for 90% of its delegates, it’s in person, and with more than 5,000 people expected, it’s now so big that it’s had to move to ExCel’s cavernous Dockland Halls. It’s 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, it’s great to catch up with old friends, but it’s 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 we’d 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 England’s 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 name’s Vivienne Parry, I’m head of public engagement at Genomics England, and I’m delighted to be your host for today’s pod from the Festival of Genomics. Welcome to you both. So, let’s 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. It’s a really large, high quality event that brings together commercial and academic and biotech companies in the one forum, and I think it’s a really exciting programme.
Vivienne Parry: And of course, Louise, it’s open to patients as well, which makes it an unusual event.
Louise Fish: Absolutely, and it’s brilliant to have patients and families here. So, people living with genetic conditions clearly need to be part of the debate when we’re talking about developing new services, and developing new treatments and diagnostics, so it’s absolutely fantastic to be able to come together in one room with people from the NHS and the broader sector.
Vivienne Parry: And it’s grown enormously, and I guess that reflects, as much as anything else, just how exciting genomics is. Matt, I’m going to pin you to the ground [laughter] and say, why is it so exciting in genomics at the moment?
Matt Brown: Look, the field’s really hitting its tracks. We’re 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 we’re 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, there’s 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, that’s the really exciting thing is we’re 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 that’s 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 they’re 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 that’s sometimes about treatments, you know. For some conditions, it’s about treatments, but it’s 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 you’ll need throughout your lifetime. So, treatment’s 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, let’s hear the first of our three clips. The programme is absolutely vast, but these were three presentations that we just thought were terrific. Let’s hear the first one.
Nagy Habib: My name is Professor Nagy Habib. I’m 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 couldn’t 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 can’t 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 don’t 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 doesn’t 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 that’s 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 it’s very expensive. Who can afford £600 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 Alzheimer’s disease. So, Alzheimer’s disease, as we get old, there are toxic materials that are accumulating in our brain cells, and only this year we’ve got two drugs coming along that can help stopping Alzheimer’s 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 Alzheimer’s 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 doesn’t even need an injection in the arm vein. So, it’s all very, very exciting.
Vivienne Parry: That is so fascinating. It’s real future casting. Matt, I mean, I say it’s 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 that’s one of the big excitements is that we’re not only being able to diagnose people, but we’re 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 can’t just basically translate what was used for common diseases into the rare disease space. It just doesn’t work, and that’s 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 don’t continue to see rare therapies falling over because they’re 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 we’re 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 don’t have the same evidence base for treatment that’s 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. They’re going to need to be able to extrapolate the benefits of that treatment across someone’s lifetime, and that can be challenging, and we’ve 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 we’re 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, it’s great to see this debate taking place early, and we’re 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 we’re 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 they’ll need, the extra support from schools and colleges, the extra support from employers if they’re able to go in employment. So, I think we’re 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 they’re making decisions about a new treatment that could be totally game changing for someone’s 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 couldn’t possibly afford it. I think it’s 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 Alzheimer’s, 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 it’s about picking up signs of diabetes using genomics ten years in advance. Just listen to this.
Harold Sneider: Hi, I’m Harold Sneider, I’m 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, it’s 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. It’s like an early detection mechanism. At the same time, a combination of these markers together lets you calculate what’s 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 – 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 it’s 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 you’ve got a much better chance of preventing end organ damage, and secondly you’ve 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, there’s 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, that’s the kind of space that we come from, and obviously in our space, the excitement is around the work that we’re 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, that’s not just about treatment, it’s about whether there’s 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, you’d be able to teach their parents to handle them safely, so they didn’t have breaks in their bones as babies, which is what we see now.
So from our perspective, it’s obviously different to the polygenic risk scoring, but again it’s 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 you’ve 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 it’s 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, ‘cos there’s 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 don’t 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, that’s 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 Study’s looking at 200 conditions and whether it’s possible to screen for them. And for all of those 200 conditions, it’s a really exciting opportunity to see if we can learn more, both about the potential to understand and develop treatments early, but also just about the chance to understand the natural history of that condition so much earlier than we do at the moment. And I think that’s it, it’s that understanding 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 there’s 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 there’s 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, I’d highlight, for example, the treatment of sickle cell disease, an absolutely massive global problem, and now we’ve got a therapy which can really control sickling crisis and make a big difference to a disease which isn’t just a disease of developed countries, in fact it’s particularly a disease of Africa, of course. On a global level, that’s 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 you’re 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, I’m 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: Let’s move to a completely different area, one that’s very important to Genomics England and less important, Louise, at the Genetic Alliance UK, which is cancer. We’re going to hear from Lennard Lee about cancer vaccine.
Lennard Lee: I’m Dr Lennard Lee, I’m a medical oncologist, so I practice as an NHS doctor, treating cancer, and I’m an associate professor at the University of Oxford. We’ve come to a position whereby vaccines can be developed quicker than anyone thought. In the last few years, we’ve realised that the technology has moved on rapidly, MRNA technology, and you can make vaccines and update them really, really quickly. We’ve 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 we’re finding now is that the technology now exists for you to print off an MRNA vaccine for that patient, a truly personalised product. And it’s 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 that’s 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 it’s based on their genetic sequence, so it’s used to treat people with cancer. The future’s 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 we’ve 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 years’ time, we’re 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 cancer’s 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 we’re going to be talking about this in this festival, and it’s being driven as from the UK, which has got so much strength in terms of genomic capabilities as we’re 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 it’s 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 there’s clearly a huge clinical trial programme that’s going to be required to drive this, and the UK is playing a really central role through the Cancer Vaccines Launchpad that Lennard’s involved with running, in creating the evidence base about whether these are going to achieve the promise that they hold.
I also think that they’ve got a lot of possibility for inherited cancer types. For example, I think the programme’s looking at cancer vaccines for Lynch syndrome, to try and prevent colorectal cancer in that group of patients. So, I think they’ve got lots and lots of opportunities, and it’s 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 you’re right, it’s 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. I’ll just give them a quick shoutout in case anyone listening is not aware of them and their amazing work. But you’re right, I think there are a couple of things going on that are really exciting in the cancer space. It’s 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, that’s a really important part for everybody. I think there’s 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 it’s been really hard to understand why that’s 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. They’re 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 it’s 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 you’re 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 you’d give it to fewer people, they’d 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, it’s not of course simply about identifying, you know, what the cancer is like and its genomic makeup, but actually it’s that wider field of pharmacogenomics, which is a big feature of the programme at the Festival of Genomics this year. And we’re very much involved in that, aren’t 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 we’re 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 they’re 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, we’re 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, you’ve already identified one area which you think is going to be big in the next few years. You’re both absolutely in the centre of the genomics ecosystem. What do you think we’re going to be seeing at next year’s Festival of Genomics? What do you think is going to be the big thing that’s coming up on the inside rail?
Matt Brown: So look, I’d like to say what I think’s going to be in next year and what I think’s going to be in ten years. Next year, I think the big things are going to be advances in AI and genomic analytics. That’s really ramping up fast, and I think we’re 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 years’ time, the two areas that we’ve 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 you’ll 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 they’re being applied in clinical practice. So I think from my perspective, it’s 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 it’s benefiting people living with rare conditions and their families through clinics across the UK and the NHS. Next year, I’d like to hear that excitement when people are talking about how it’s actually affecting real lives. In ten years’ time, I hope we’ll be talking about the massive difference that some of the amazing techniques we’ve heard about here this year have made to the lives of people living with genetic and rare conditions.
So, you know, in ten years’ time, I hope that some of the treatments and the opportunities and the tests we hear about today, we can see how they’ve 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 we’re hearing about today.
Vivienne Parry: Fantastic. It’s 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 you’re interested in things genomic, you can subscribe to the G Word on your favourite podcast app, and if you’re new to our podcast, and we always welcome our new listeners, do check out our back catalogue. You’ll find it’s really extensive. There’s a wonderful set of genomic listening available to you, in which even spatial transcriptomics gets explained. I’ve 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.
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, it’s 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 it’s 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 don’t have a specific treatment. This is a very good question, and I would like to note that it’s 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 that’s 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. I’ll start by saying that there are lots of rare conditions that aren’t genetic, and there are common conditions that do have a genetic basis, so none of these observations are absolute, but there’s 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 it’s important to say that there’s a lot that we collectively don’t know yet about rare conditions, so our understanding is incomplete and imperfect, and there’s 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 don’t have a specific treatment. There’s 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 I’m 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. I’ve 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.
