In this episode, we explore the importance of patient involvement in shaping rare condition research initiatives. Our guests discuss why it’s crucial to involve individuals with lived experiences, including patients and caregivers, in setting research agendas. In doing so, this approach ensures research can be more inclusive, efficient, and impactful, addressing the issues that matter most to those affected.

Mel Dixon, Founder Cure DHDDS and member of Genomics England Participant Panel is joined by Jo Balfour, Founder of CamRARE and Dr Rona Smith, Senior Research Associate at the University of Cambridge and Honorary Consultant in Nephrology and Vasculitis.

Find out more about the Cambridge Rare Disease Research Network, discussed in the episode, which aims to support the rare condition community in building an online network of partnerships and resources to facilitate new patient-centred research opportunities.

"We’re really turning research on its head, moving away from it being a researcher-led activity where they decide on the idea and the research concept and bring patients in at different points along that research journey and instead starting with the patient’s idea in the first place.  It can only be a better system for all because it improves efficiency, it improves potentially the long term outputs and, most importantly, outcomes for patients."

You can download the transcript or read it below.

Mel: Welcome to Behind the Genes.

Rona: I think it really means that we measure what matters to patients and individuals that are affected.  Often, it’s really difficult to capture kind of the real impact of disease and there’s a tendency for researchers to measure things that are easy to measure and are reproducible, which of course is important but what’s most important is actually being able to truly capture the impact of an intervention on an individual’s condition.  So, I think that’s another key aspect of having people with lived experience involved right from the start.

Mel: My name is Mel Dixon and I’m a member of the Participant Panel at Genomics England and founder of Cure DHDDS, a charity set up to raise awareness, support families and help drive research into the ultra-rare DHDDS gene variant.  On today’s episode I’m joined by Jo Balfour, Managing Director of CamRARE, which is the Cambridge Rare Disease Network.  This network unites patients, advocates, experts and leaders to address the challenges faced by people affected by rare conditions.  I’m also joined by Rona Smith, Associate Professor at the University of Cambridge and honorary consultant in nephrology and vasculitis.  Today we’ll be discussing the role of patients in setting research agendas and how their involvement can lead to more impactful and patient-centred research.  If you enjoy today’s episode we’d love your support.  Please like, share and rate us on wherever you listen to your podcasts.

Before we begin the interview I’d like to share a little bit of my story.  In November 2022, following whole genome sequencing, we received the news that two of our three children carried a neurodevelopmental and neurodegenerative DHDDS genetic variant.  At the time of our children’s diagnosis there was very little information on our gene, minimal research happening into it and no treatment pathway.  Through our charity, Cure DHDDS, we have worked tirelessly to instigate research and create a collaborative scientific research community.  I am a huge advocate for patient-led research and have witnessed first-hand the positive impact it can have on patient lives.  Thanks to the work of the many scientists that we have had the honour of collaborating with, within two years of our children’s diagnosis we have a disease-modifying therapy in our sight and an ASO (Antisense oligonucleotides) therapy in development.  We are incredibly grateful for the opportunities genetic testing has given us but I also appreciate how overwhelming a genetic diagnosis can be and how challenging it can be for families to initiate research projects with little to no resources, and that’s why initiatives such as CamRARE that we’ll be discussing today are so important.  

On that note, let’s get back to our podcast guests.  I wonder before we dive into today’s topic if you could both give a brief introduction, and, Rona, if you could also give the less scientifically-minded of us an explanation about what nephrology is.

Rona: Thank you for inviting me today.  So I’m Rona Smith, I work in Cambridge and I’m a nephrologist and that means somebody that looks after individuals who have diseases that affect their kidneys.  My specialist interest is in something called vasculitis which is a rare autoimmune disease that affects all organs in the body but kidneys as well. 

Mel: Thank you.  And Jo? 

Jo: Hi Mel.  I’m Jo Balfour, the Managing Director and one of the founding members of Cambridge Rare Disease Network, or CamRARE for short.  I think we’re often described as the ‘Chief Everything Officers’.  I manage the charity and all of our operations and our wonderful team.   

Mel: Lovely.  Thank you very much.  Rona, I wonder also if you could explain to our listeners what is a research agenda? 

Rona: So in brief a research agenda is really a strategy that outlines key questions or topics that a research community, and that might be investigators, clinicians, scientists, patients, industry,  and they are the priorities that they want to explore and address over a period of time.  So it’s really a direction of travel and identification of areas of importance and where there are gaps in knowledge so that it then leads to the opportunity to form specific research questions that you can then go on and address. 

Mel: Why do you both think it’s important to involve patients in setting these research agendas? 

Jo: Well I think critically one of the things that I’ve learnt over my time working, not just in the rare disease sector but also earlier in social care and education, is that we should as professionals never assume anything; you know, we have not lived in their shoes and we don’t know what the daily life of people living with rare conditions is like.  So gathering that day to day lived experience is really crucial.  And I have a unique opportunity to see into that daily life with our local community of rare disease families who have a range of different rare conditions.  I’m party to their conversations, to their daily trials and tribulations, the things that are difficult, the things that they find joy in but I still will always go back to them and ask their opinion.  I see myself as a spokesperson for them as we’re an umbrella organisation but I certainly never really know what it’s like to live with their conditions.  I think they bring with them diverse experiences which we really need and value in setting research priorities, they have unique knowledge of their own conditions.  They ethically have a right to be involved from the start and to set that priority and agenda but, equally, it’s valuable for us as researchers because if we can involve people early we have definitely more chance of good engagement and later success, better outcomes for everyone. 

Mel: Couldn’t agree more.  And, Rona, is there anything you’d like to add to that?

Rona: I think it really means that we measure what matters to patients and individuals that are affected.  Often it’s really difficult to capture kind of the real impact of disease and there’s a tendency for researchers to measure things that are easy to measure and are reproducible, which of course is important but what’s most important is actually being able to truly capture the impact of an intervention on an individual’s condition.  So I think that’s another key aspect of having people with lived experience involved right from the start. 

Jo: Another thing that’s actually quite interesting that I’m going to mention here is that I think when you live day in, day out with a condition your perception of things like pain is different from your average person’s so you become almost accepting of your daily norm, and I think that’s really critical to understand as well.  And it’s only by getting to really know patients and understand. When we say, “What’s your pain like on a scale of 1 to 10?” you know, something that I feel as pain because I get it rarely I probably am going to put it at a higher score than somebody who has that every day.  So I think there’s subtleties and nuances like that as well which are really critical to get across by conversation with patients. 

Mel: That makes absolute sense.  And I see that from the patient perspective myself.  I was out with my friends the other day and they said, “Oh my goodness, you’re constantly taking your children to sports activities.”  Because of their physical needs we’re constantly,  they go to Pilates, they go to swimming, they go to gym class – we try to keep them fit and healthy – and we, even though they’re older, have to take them there and back and that’s become our norm but when you’re speaking to families whose children don’t have those difficulties they have no idea how much time that actually takes up.  And I had no idea how much like time it takes up compared to what other people are doing because that is our norm, that’s what we’ve accepted as the norm.  Patients and patient groups are incredibly driven and invested in their rare disease as well so they make really good rare disease research partners.    

And, moving on, what do you see as the challenges and barriers to patient involvement and how do we overcome these?

Rona: I think probably the biggest barrier is time.  So, the most important thing is investing time to build relationships, to really understand in-depth perspectives both from the patient’s side but also the researcher’s side. And, inevitably, we always want to do things faster and actually this is one really, really critical aspect is investing time.  Funding is also a challenge.  Often you have to do a lot of upstream work before you have got funding for a project and that takes time from individuals and that’s another challenge.  And I think the third thing for me is individuals that are patient partners in research, they’re not just patients, they’re people - they have lives, they have work, they have families, they have everything else that goes on in life - and so actually fitting this all in is really challenging. 

Mel: Jo, is there anything you’d like to add there? 

Jo: Yeah, I think just a word about diversity really and, you know, how do we uncover those hidden families and patients who currently don’t really have a voice.  I think we’d all acknowledge that there are key voices within the rare disease community who will share the views of their community and they’ve become well-oiled machines almost at being great advocates but, as I mentioned earlier, even though I’m perhaps one of those people, you know, I speak for a community, I would never assume anything.  So, I still need to uncover the thoughts and the feelings and the emotions and the needs and the what matters from those people, and, as Rona mentioned, that takes time and it takes building relationships and trust with people.  So, we have a wonderful community in the Eastern region of England which is made up of families affected by all different rare diseases, and undiagnosed.  And some are babies and have been lucky enough to get a very early diagnosis and others are young adults but what we’re finding through that is that experience is diverse and experience changes over time as families go through transition periods or they meet a roadblock and they’re having to navigate things differently.  So, it’s about building those relationships.  That takes times, it takes resources, it takes sometimes a reset in the way that we think things need to be done.  So instead of asking questions all the time and putting surveys out and trying to get response that way it takes a bit of thinking about how do we listen better and how do we give those people who don’t have a voice, who are non-verbal or perhaps have a learning disability, how do we ensure that we’re capturing their views as well.   

And we did a really lovely project actually last year, it was something funded by the NHS called My Story, My Way, where we actually spent three months with our young adults working out what it was they wanted from our community next, how did they want us to follow them into adulthood.  And we knew that there were a number of young people in that group who were non-verbal and had some learning differences and we knew that we couldn’t just do it in the normal format, we couldn’t just do a focus group and ask their opinion, so we actually did it through photography.  So each of the familiess well, the young person themself was given a simple camera.  They basically had thirty-six shots.  You got thirty-six clicks to capture the things, the people, the places that you love and then to share them with us as a community.  And then we all discuss, you know, how these things might be something we can build into our future plans for them.  And it was such a wonderful activity.  We gave them plenty of time, plenty of opportunities to ask questions.  If the young person themself couldn’t physically click the camera their sibling got to help them.  And their sibling or their parent was given another camera in black and white so we had distinctive pictures, pictures that the kid themself had taken, pictures that the family had taken, but all together, you know, it gave this lovely kind of medley, this beautiful visual representations of what mattered to them.  And I think it’s about taking the time to be creative with people like that and really get to the bottom of “How do we find out what matters to you?”

Mel: Although it takes time to think about those ideas.  That could be translatable across the board really, couldn’t it, throughout various conditions.  I think that’s fantastic.  Rona, I wonder if you can tell us how has the work that’s already been done through the patient-led research hub facilitated addressing research priorities. 

Rona: So just a tiny bit about the patient-led research hub.  So, this has been now running for nearly ten years through Cambridge.  It’s a partnership between the Cambridge Biomedical Research Campus and we’re based within the university and the Trust.  And in essence it kind of was set up because of really a mismatch between what many patients wanted from research and what investigators’ views were.  And so really the premise is that we welcome patients to come to us with an idea, a problem, an unmet need in their disease area – and we do focus on rare disease – and we work with them to see “Well actually what do we already know about that?” and then if there is a gap in knowledge we then move to kind of trying to work and develop a question that we can then address.  And that might be a question that’s addressed through generating more information through surveys or it may actually be a question of an intervention that we can test. 

So, we’ve had lots of projects come through and we, just an example of a project was from a group of patients with a rare kidney condition called autosomal dominant polycystic kidney disease, and that is a condition where over time you accumulate cysts in your kidneys and the kidneys become large, they become very painful and eventually they can fail.  And a question that the patient group had was about whether drinking more water could impact the rate of growth of these cysts, and there’s a strong hypothesis behind that that drinking lots of water reduces down the level of a particular hormone.  And we actually worked with the charity behind this group, the Polycystic Kidney Disease Charity, and designed a study to test a very high water intake to a normal water intake to see whether it was possible over a period of eight weeks for patients to actually stick to this.  It’s quite difficult to do.  And they recorded how much water they’d drunk, they tested their own urine and actually it showed that this was feasible to do this kind of work.  So, I think the patient-led research hub is kind of taking the research priorities that are important to patients but working in a patient-led way to come right through to a project. 

Mel: That sounds great.  And if the patients are engaged from the start of the project and it’s led by them they’re obviously going to be much more driven to take part in the actual research and see the research through themselves.   

So, Jo, I’m very excited to hear about the launch of the Rare Disease Research Network.  Can you please tell me what the research network is and what you hope to achieve with it? 

Jo: So the Rare Disease Research Network is first of all a bit of a mouthful so we’re going to try and encourage people to call it the RDRN.  It’s a co-created project which really the patient-led research hub in Cambridge approached us about in 2022, I think, we started talking about this, approached CamRARE as a partner to apply for an NIHR partnership grant, and we were successful with that to really take the model that the patient-led research hub had already developed and found was successful, and perhaps too successful for its own good – they were receiving more applications and more ideas than they could manage – and to develop that into an online platform.  So taking the same model, making it more accessible to a wider group of people, potentially worldwide, and providing the hand-holding that the patient-led research hub has always done, helping patients really consider their question, formulate that into a research idea, then do the literature search to find out “Is this question already answered, and if it is, great, can we provide that information to our community?  If it’s not, how do we then build a team?  Who needs to be in my research team?  How do we then get funding together to take this idea forward?”  So, it’s really taking the model, taking the good practice that already existed and creating an online platform to really attempt to replicate that as best we can.

So the platform will launch on 23rd November (2024) at CamRARE’s Rarefest which is a lovely in-person activity that’s going on in Cambridge, and that platform will be open to anyone who has an interest in rare disease research.  But I think, critically, what’s different about this is that, you know, we’ve talked about setting research agendas and we’ve talked about patients contributing to that, contributing to setting the priorities, what’s different here is that the patients decide on the questions; it’s what matters to the patients coming from them and their community.  And it’s an opportunity for them to showcase those questions and those idea on a platform and almost to have a call to action, “Is there anyone else on this platform who has similar research interests to me?”  The platform will matchmake them together through a series of choosing tags, choosing tags about particular disease areas -  It’s linked to the Orphanet database - choosing tags about the type of research that you’re interested in.  That matchmaking process will happen, which at the moment is a very serendipitous process but we hope to take it a little bit further on from that.  It’s still going to be a little bit of potluck who’s on the platform at the time who’s got similar interests as you but hopefully it will improve that serendipitous system.  And it will allow them to access resources on the platform, which is the kind of hand-holding bit, and also, critically, some mentoring.  So, there’s a real sort of opportunity here for professionals – researchers, industry partners, healthcare professionals – who have particular skills in research to be able to say, “Well I can help.  I might not be able to be part of your team at this point but if you need half an hour on a Zoom call with me to think about your research question I can offer to mentor you on that.” 

But, likewise, I think there’s going to be lovely opportunities here for patient groups to support each other too because what we’ve always realised is that patient groups are at different points of their research journey.  You know, we see some organisations that are really well-funded now who are in partnership with industry, you know, they have a group of pharma companies that are supporting the development of treatments and they’ve kind of reached that point where they’re very highly skilled and very well experienced.  And then there’s others who are mum and dad who’ve just had a recent diagnosis for their child, they’ve gone searching on the internet, they can’t find information, they don’t have a patient organisation to rely on so they’re going to make one themselves.  This happens all the time in the rare disease field.  There are 11,000 different rare conditions and there’s not a group for all of them so mum and dad will often start something themselves and then in lots of cases want to do some research, they want to answer some of these questions.  So, you know, they’re really starting from a very different beginning stage here where they’ve going to need some help, and sometimes the best help comes from their peers, it comes from other patient groups.  So that’s in a nutshell what it’s about; it’s about providing opportunity for patient groups to showcase their great ideas, build partnerships and take research forward.  

Rona: The only thing just to add there is I think, although rare diseases are individually rare, collectively, as Jo said, they’re quite common, there’s 11,000 rare diseases, and often, although they all have distinct features, there are common threads through rare diseases in terms of maybe symptoms that patients experience or challenges that their rare disease brings.  So, for example, you may have symptoms of pain or seizures that are common across many conditions, there may be educational needs that are threads going through.   And groups could work together maybe to answer a question that’s relevant to a number of conditions and so bringing people together for that.  Or there may be another group that’s already tried to answer that question in their condition and you can learn what worked, what didn’t work.  I think that’s the other thing, is there will be common threads that come through, and I think that would be a real strength of the network to draw those people together.

Jo: I think as well, Mel, if we take this back to what we said right at the outset about optimising success for patients by bringing them into the conversation early, I think this platform provides the perfect opportunity to do that.  So we’re moving away from, we’re really turning research on its head, moving away from it being a researcher-led activity where they decide on the idea and the research concept and bring patients in at different points along that research journey and instead starting with the patient’s idea in the first place.  It can only be a better system for all because it improves efficiency, it improves potentially the long-term outputs and, most importantly, outcomes for patients. 

Mel: We were that family, that mum and dad setting up the charity a year and a half ago for the ultra-rare disease that our children had.  I think, you know, the match-making opportunities that are here are fantastic because finding yourself in that position is incredibly isolating.  And not only the matchmaking opportunities with the researchers but, as you were saying, Rona, as well with similar diseases; there’s so much to learn from other diseases that may have, I don’t know, a similar phenotype in the cells or similar symptoms.  That’s what we found from connecting with these other rare conditions.  So, for us it’s lysosomal storage diseases, we’ve now got the opportunity potentially to piggyback on drugs better used for their diseases for our own ultra rare condition, you know, where for us to run a full-on clinical trial by ourselves with a new drug, I mean, we just wouldn’t have,  there’s no funding, there’s not enough interest.  So, I think the opportunities that lie in this network are really, really exciting.  Jo, can you tell me a bit more about who can join the research network? 

Jo: So anyone with a rare disease research interest. That’s everybody from individuals affected themselves, their family members, their caregivers, the patient organisations, that support them, and then, you know, all sorts of rare disease professional researchers.  So, we’re looking for PhD students who are looking for their first exciting project to undertake, have they taken a look at the Rare Disease Research Network to see if there’s any ideas that might pique their interest.  We’re looking for established researchers, medical professionals who are undertaking clinical research but also I think, importantly, companies.   You know, we hear more and more about concepts like drug repurposing for rare diseases where we’re looking at the opportunities for taking drugs that already exist and have been proven safe to be redeployed to other rare diseases. It’s quicker, it’s more efficient, it’s cheaper, so does it open up opportunities for companies that are using that technique to get involved.  And also pharma companies.  This platform is not all going to be about finding cures and treatments but it certainly will be a priority for some groups.  So we really are welcoming everyone with an interest in rare disease research to get involved, be part of the network, collaborate, help where you can.

Rona: And also, as we’ve said before, once you’ve got that level of engagement and the patients leading these initiatives we’ve found, certainly with our group, the patients are much more willing to, say, find the MRI scans for the scientists, to have a blood sample done, to have skin fibroblasts taken.  If they know and they understand and they’re driven and, as you said, the research idea has come from them as a patient group it certainly increases the chance of them being fully involved in the project from the start to the finish.  And all these things are imperative to understanding rare conditions because without researchers having the opportunity to look at these various samples you’re not going to stand much of a chance of finding a treatment. 

Jo: And we want the opportunity to upskill patients as well.  I think there are many people out there with great ideas who haven’t yet found the confidence to promote those ideas because they’re not quite sure of what the research journey looks like or what it might entail or whether they’ve got the right skills.  But I think by joining the platform and almost kind of watching how other people are managing these things and utilising the resources and the mentoring I do really hope that will build that confidence and those skills sets in people so that they can engage. 

Rona: Yeah, just to add to that, I don’t think it’s just upskilling patients and patient groups, I think it’s upskilling everybody involved in rare disease research.  This is quite a different way of approaching research, it’s something that maybe academics may feel a little bit uncomfortable with, it’s not how it’s normally done, so I think there’s a whole learning process.  And the aim is that this RDR network will evolve and will develop and the direction it goes will be driven by the community that are engaging with it.  So I think it’s a really exciting time just as we’re coming up to launch to see where this goes. 

Jo: Mel, you’ve been involved in this project, it would be really interesting actually to hear from you. I was just thinking, as part of the co-creation community we had 25 individuals from the rare disease community who built this platform from scratch with us; Rona and I might have set out all the vision for how we wanted the platform to be or what we thought might be a good idea but ultimately it was the community who decided and they literally have fact-checked and cross-referenced every word that’s gone on the platform. What has that experience been like for you as a patient representative? 

Mel: I think it’s been really welcome to see a network that is truly putting patients at the centre of everything.  So, from the very beginning foundations you have the rare disease community involved which is exactly what you’re trying to create through your network.  So, I think it’s been very welcome to be involved in the project and I also think that hopefully it will sort of be self-perpetuating that this will start to press a reset button on how we think about rare conditions and how it needs to be a more equitable field with patients.  Because I think, as you’ve both alluded to, while some clinicians and researchers are very onboard with this, for others it’s a new concept that they still need to potentially adjust to or get their head round because it is a different way of thinking.  But in rare disease, well, in any condition really but particularly rare disease because there’s so few experiences to draw on, I think that patients are vital to moving forward and to making that change so that diseases and conditions that have previously had no treatment, like, hopefully this way of thinking can expedite those treatments because, well, as a rare disease representative myself for our community that’s one of our biggest drivers.  We’re dealing with a condition that’s progressive that affects most of our community’s children; that is what we want, we want treatment, we want something that can stabilise the conditions.  You know, you can have researchers doing random projects that would make no difference to the final outcome of patients but if researchers know it’s a priority of this particular group, hopefully that can channel in their focus and get the outcomes that the patients want in a more timely collaborative way.  So, I am a huge advocate for what you’re doing, I think it’s an incredible initiative.  Is there anything either of you would like to add to that?

Rona: Rare disease disproportionately affects children and young people.  So, 7 out of 10 rare diseases develop in childhood and at the moment the Rare Disease Research Network hasn’t really got a forum for including children and young people, and really that’s partly because, and Jo can speak much more eloquently to this with her experience.  Actually, we didn’t do that at the start because we feel that this is actually a discreet piece of work that really needs to be done in collaboration with children and young people to make sure that it’s done well so that they can engage in the platform. So, Jo, I don’t know if you want to talk about how we’re hoping to take this forward. 

Jo: Yeah, so we’re busy developing a project plan at the moment which we’re hoping to get funding for to work over eighteen months with a team of young adults with rare conditions, probably from our Unique Feet community and keep it local because we already have a good relationship with them and they have our trust.  But the idea would be to work with lots of other young people’s forums.  So there’s already ones established in and around our area, such as Pedal, which works with really small children, and there’s also groups that are set up for young people with cancer.  So we’ve already had lots of great conversations with them about how we can work with them, how they can help us sense-check our project, and then in return we can help them better understand research and their ability to be involved in that.  But ultimately by the end we want to run focus groups, we want to develop some peer mentors within our community, so young adults who’ve, you know, perhaps come out the other end of a period of transition into adulthood who can support other young people with rare diseases to also become researchers, to come up with their own ideas and their own questions, and to sense-check projects that come through the platform.  So it’s a really exciting opportunity to truly involve the people who are affected most by rare conditions but we know through our My Story, My Way project that this has to be done gently, carefully, given time and done really thoughtfully.  So that’s our next step and we hope to be able to share those learnings with people so that it can be done elsewhere. 

Mel: And do you see the network also working with children with learning differences?

Jo: Absolutely.  We’ll invest a lot of time and energy in ensuring that materials are accessible, inclusive and suitable for the community that we’re working with. 

Mel: So looking to the future, how do you think, Rona, can patient-led research help to shape the future landscape? 

Rona: So I think, Jo used the term earlier, kind of this is really turning research on its head, so it’s really putting patients right at the centre of research, so it just makes sure that it’s absolutely driven by what matters to them to get the outcomes that matter.  And, again, it’s just got all that benefit of efficiency and really answering those questions that matter. 

Mel: And, Jo, do you think this could lead to more collaborative partnership, for example, between industry and academia, potentially leading to quicker clinical advancement?

Jo: I would absolutely like to think so.  You know, as CamRARE we run a companies forum which is a roundtable meeting for pharma and biotech companies and other organisations like Genomics England who are involved in the rare disease therapeutic space and diagnostics, and I think one thing that I find really heart-warming about those meetings is that, you know, different companies are able to sit around a table as competitors but with a very open mind to addressing the barriers and the bottlenecks that prevent them from getting drugs to patients.  Because of course it’s not just the research journey that’s a challenge, it’s the regulatory side of things at the end of that journey; just because you’ve created a great drug it doesn’t matter in the end if it doesn’t get to the patient.  So, you know, access is critical and involving patients at the earliest possible moment to ensure that that treatment gets through to the regulators and gets access to patients is the only way forward. 

We had a recent companies forum meeting where we were exploring health-related patient reported outcome measures, or PROMs, and we had a speaker from NICE who’s the regulatory body, we had a speaker from Sheffield University who was talking as an academic about developing PROMs for industry and for patient groups and we had Emily Reuben, the CEO of Duchenne UK, and we had an amazing discussion about the importance of involving the patient community from the outset.  And the academic explained that developing a PROM for Duchenne UK had taken them two years and it had taken them that length of time because they’d followed this careful thoughtful pathway of making sure that they didn’t assume anything about what matters to patients.  But that of course, as we said earlier, involves time, it involves financial commitment, it involves resources and the right attitude, but I do think that a platform like the Rare Disease Research Network can really try to harness all of those things by bringing the right people together – industry, academia and patients – to work together equitably.

Mel: And with the network do you think you’ll be getting the regulators in at that initial stage as well so that, like you said, the patients can gain access while we’re dealing with their priorities, the regulators are informed at the very earliest stages so that we know the process that’s being followed will ultimately lead to patients gaining access to the relevant therapies? 

Jo: Yes, I think this is really important, and there’s actually, we’ve got a section on the new platform which really talks to each of the different stakeholders.  ‘What’s in this for me?’  ‘Why is it important for you to be here and to join?’  And one part of that is funders and that includes the regulatory bodies.  And at the next companies forum meeting we’re actually going to be bringing the Rare Disease Research Network Platform and its potential to the companies forum meeting and we’ll have regulators involved in that.  So, you know, we are constantly talking to people about why it’s important for them all to be involved and all to see what matters. I think I’d like to advocate for an extra letter at the end of PPIEP - if we could squeeze a D in there at the end too.  So over time that terminology has expanded to be Public Patient Involvement Engagement and Participation, which was added I think this year, but it would be lovely to have the D on the end and to include ‘Driven’ because I think what’s really important about this platform is that it’s not just engagement and involvement, it’s not just participation, it’s initiated by and driven by patients.

Mel: So I think we’ll wrap here.  Thank you to our guests, Jo Balfour and Dr Rona Smith, for joining me today as we discuss the role of patients in setting research agendas.  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, Mel Dixon, and this podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand. 

In this explainer episode, we’ve asked Meriel McEntagart, Clinical Geneticist in the NHS and Clinical Lead for Rare Disease Technologies at Genomics England, to explain how genetic conditions can be inherited, and other ways they may arise.

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 [email protected].

To learn more about X-linked inheritance, as mentioned in the episode, tune in to our explainer episode, how does X-linked inheritance work?

You can download the transcript or read it below.

Florence: Are genetic conditions always inherited from parents? I'm joined by Meriel McEntagart, clinical geneticist for the NHS to find out more. So, Meriel, first things first. How can a genetic change cause a condition?  

Meriel: We have about 20,000 genes. That's the estimate and they are the code or blueprint for how to grow and develop a human being. And, if you think about a code, you can have a mistake in a code or a variant in a code. And if that happens, such as one genetic letter being changed for another, the result can be that the code doesn't give the correct instructions about how to grow and develop that human being. There are lots of different ways in which those changes can happen. 

Florence: And how can we inherit conditions from our parents?  

Meriel: Well, for the most part, like I mentioned, we've got 20,000 pairs of genes and we get one of each pair from our mother and our father. And so, for lots of genetic conditions, they follow a pattern of inheritance where one copy of that pair of genes has got the variant or spelling mistake in it, which causes the condition. 

So just having a single mistake in that pair of genes is enough to cause you to develop the symptoms of the condition. Other conditions show where you only develop the condition if both copies of the pair, the one you get from your mother and the one you get from your father have got a variant or a spelling mistake in the gene. 

So, you actually don't have a working copy of that gene. There are other patterns of inheritance as well. And so, we talk about X-linked inheritance. That can arise because women have what we call two X chromosomes; men only have one X chromosome. 

Florence: If you want to learn more about X-linked Inheritance, you can check out our previous podcast. How does X-linked inheritance work? So then do parents who have a condition always pass it on to their children? 

Meriel: So, this is again, where we think about some of those patterns of inheritance that I've just mentioned. If somebody has a condition, for example, a dominant condition, they will have that variant or genetic change that's causing their condition in one of their pair of genes. So then it's 50:50 when they have a child, whether they pass on the gene that's carrying that variant or not, because the child will be getting the other copy of that pair from their partner. 

If they do inherit that copy with the variant in it, then they will develop the symptoms of the condition in most cases. In some situations, however, a parent can have a genetic condition. So, they develop symptoms of the condition, and as I've mentioned, it's 50:50, whether it gets passed onto the child, so the child could actually inherit that genetic variant, but potentially not show signs of the condition. And this is what we call ‘reduced penetrance’. This means you can carry a genetic variant and probably some other event has to take place to cause you to develop symptoms. 

So that might be that there's other genetic factors that you inherit that trigger you to develop symptoms or there might be an illness or something that you experience that brings out the expression of that gene. So that's quite an important, consideration when we're looking at genetic variants and whether somebody will develop symptoms. 

Florence: And finally, how do we develop conditions that don't come from our parents? 

Meriel: Well, I suppose the main explanation for that is what we call a de novo genetic event. So that can arise when we are conceived. So for example, genes get copied to be put into the sperm or our genes get copied to be put into the egg. And in that process of making the sperm and the egg, a spelling mistake or mutation can arise in the DNA and then that sperm or that egg, whichever one has it, takes that forward into making the baby. And then the baby from that point will have that genetic variant in every single cell in their body. So it hasn’t come from the parents, so it’s not inherited but it still is a genetic condition.

This is something that now that we're able to do whole genome sequencing, we are finding is a more common explanation for developmental disorders or conditions in children than we previously appreciated. And quite a lot of conditions where the child has congenital abnormalities when they're born, like a congenital heart problem with some global development delay or difficulties or some other sort of problem, when we do their whole genome sequencing, we find that they have a de novo mutation in an important developmental gene. 

There are also some more unusual ways in which a genetic condition can arise for the first time in the family. The first example I might give is, the condition, Huntington's disease. Huntington's disease is a neurodegenerative condition that causes a movement disorder, often starting in adult life. And sometimes people will know that it's in their family. However, sometimes it can arise in somebody and there's no history of it in the family at all.  Huntington's disease is what we call a triplet repeat condition. This is where, in our DNA sometimes we have little strings of letters that are repeating after each other. So, usually we'd have 25 repeats or less. This can slip up on transmission from a parent to the child, so it can increase in size and if it slips up into the range of 40 repeats or more, then that person will develop symptoms of the condition. 

Another example I thought that might be worth mentioning is what we call imprinting. When we inherit our genes from our parents, for some genes, it actually matters whether the gene copy has come from your mum or from your dad, and it will have an imprint or a mark on it that says, this is the maternal copy, this is the paternal copy. 

The reason that imprint is there is that it may potentially switch off that gene and say, this shouldn't be expressed in the baby. And if this doesn't work properly, you can get some conditions like for example, Prader-Willi Syndrome. This is where a child has developmental delay and maybe a very increased appetite. And it's because the differential gene expression hasn't worked.

Florence: That was Meriel McEntagart, explaining whether genetic conditions are always inherited. If you would like to hear more explainer episodes like this, you can find them on our website at www.genomicsengland.co.uk. Thank you for listening.

In this episode, we explore findings from a groundbreaking study recently published in Nature which revealed potential targets for bowel cancer prevention and treatment. The study provides the most detailed understanding yet of bowel cancer’s genetic makeup. The research, which used data from the 100,000 Genomes Project identified over 250 genes that play a crucial role in the condition, driver genes and potential drug targets. Our guests discuss the potential impact of these findings on patient outcomes, screening for bowel cancer, and future prevention strategies.

Helen White, Participant Panel Vice-Chair for Cancer at Genomics England is joined by Professor Ian Tomlinson, Professor of Cancer Genetics at the University of Oxford, Claire Coughlan, Clinical Lead for Bowel Cancer UK and consultant nurse in colorectal cancer, and Dr David Church, a clinical scientist fellow and a medical doctor specialising in oncology at Oxford University.

"The people that were kind enough to donate samples to the 100,000 Genomes Project, they did so knowing that they almost certainly wouldn’t benefit personally from their donation from their gift and that any benefits would be some way down the line and hopefully benefit others which is what we’re seeking to realise now. But, you know, it’s not a given when we treat people in the clinic so we’re very, very grateful to those individuals."

You can read more about the study in our colorectal cancer blog and our study findings news story.

You can download the transcript or read it below.

Helen: Welcome to Behind the Genes.

Ian: One of the great hopes is that some of these new genes that we’ve found could be useful in preventing cancer and it doesn’t necessarily matter that they’re rare, even if they’re only 1% of cancers, by using those and changing those in the normal individual before they have had cancer then we may be able to reduce that risk. So, there are lots of potential new targets for prevention that are coming through. 

My name is Helen White and I’m the Participant Panel Vice-Chair for Cancer at Genomics England. Today I’m delighted to be joined by Professor Ian Tomlinson, Professor of Cancer Genetics at the University of Oxford, Claire Coughlan, Clinical Lead for Bowel Cancer UK and consultant nurse in colorectal cancer, and Dr David Church, a clinical scientist fellow and a medical doctor specialising in oncology at Oxford University.  

Today we will be discussing a pioneering colorectal cancer study which using data from the 100,000 Genomes Project has uncovered new insights that could transform diagnosis and treatment for patients with bowel cancer. If you enjoyed today’s episode we would love your support, please like, share and rate us on wherever you listen to your podcast. 

Thank you for joining me today. We’re going to be discussing the findings from a landmark study that has been published in nature. This study used data generously donated by people with bowel cancer who took part in the 100,000 Genomes Project giving us the most detailed look yet at the genetic makeup of colorectal cancer better known as bowel cancer. But before we get into that let’s start by hearing from my guests. Could each of you please introduce yourselves. 

Ian: I’m Ian Tomlinson, I work at the University of Oxford and most of my work is research into bowel cancer, it’s genetic causes, the genes that are involved in actually causing the cancer to grow which may be different from genetic causes and also the use of that data to help patients whether guiding future treatments or potentially helping to prevent bowel cancer which would obviously be our optimum strategy to have the biggest impact on the disease and its incidents.  

Claire: So, I’m Claire Coughlan, I’m the clinical lead for Bowel Cancer UK and my remit at the charity is to ensure that everything we do is clinically relevant and that we’re providing services that meet the needs of those affected by bowel cancer and the educational needs of those health professionals that work with people affected by bowel cancer. I’m also a nurse consultant in colorectal cancer at Lewisham and Greenwich NHS Trust and I lead an urgent referral service there and also work with patients with late effects of bowel cancer. 

David: I’m David Church, I’m a medical oncologist and Cancer Research UK advanced clinician scientist at the University of Oxford. I treat bowel cancer clinically and do research on bowel cancer and womb cancer including a lot of research using samples and data from Genomics England data service we’re discussing today of course. 

Helen: Great, thank you. Now let’s turn to Claire to learn more about bowel cancer. Claire, can you share with us how common it is, how treatable it is and if there are any trends in terms of which groups of people are affected? 

Claire: Of course, bowel cancer is a relatively common cancer, there are about 46,000 people each year in the UK diagnosed with bowel cancer so that is quite a large number. The thing that really drives us forward in bowel cancer is that the earlier stage you’re diagnosed at the greater chance of survival. So, the figures for that are quite stark, we stage bowel cancer through stage one to 4 with one being the earliest stage and 4 being the most advanced.  

If you are diagnosed with bowel cancer at stage one you have a 9 in 10 chance of being alive and well 5 years after your diagnosis of bowel cancer. And if you’re diagnosed at the other end of the spectrum at stage 4 that drops to a 1 in 10 and should people survive after a diagnosis of stage 4, which more people than before do they will have had a lot of treatment for their bowel cancer so the burden of the treatment will also be with them after that. So, it’s really important that we diagnose at the earliest possible stage which is why studies such as the one we’re going to talk about today are so important.  

We have noticed that there has been a slight increase in being diagnosed at a younger age. That said the latest statistic is 2,600 people were diagnosed under the age 50 in the UK last year so it’s still a disease of older people, you still have a greater chance of getting bowel cancer as you get older but it’s really, really important that we’re aware that you can still get bowel cancer as a younger person.  

Probably one of the most exciting things that has happened for bowel cancer of recent years is our bowel cancer screening programme and the age for that now has been brought down to 50, we’re not quite there all over the country, but in the UK that is the aim that everyone will be screened for bowel cancer at the age of 50. So, yes it’s a common disease and staging an early detection is vital.

Helen: That’s lovely Claire, thank you very much for that. David, turning to you could you please explain to us how bowel cancer typically develops?

David: Yes, so we know compared with many cancer types quite a lot about how bowel cancer develops because the bowel is accessible to collect samples by a technique called endoscopy which is putting a camera into the bowel from which you can sample tumours or lumps. And so from genetic research done in the last 10 years we know that, or we’ve known for many years actually, for much longer, that cancer is a genetic disease, it’s a disease caused by alterations in genes and particularly genes that control whether the cells in our bowel grow normally and die normally as they should do.

And collectively when there are alterations in genes that regulate those processes you can have a cell or collection of cells which are able to grow without restraint and don’t die when they should do which are some of the hallmarks of a cancer and they also require the ability to spread elsewhere in the body which is what kills people with cancer including bowel cancer. We know from research done in the last 10 to 15 years that some of the alterations in genes that can cause bowel cancer in combination occur very early in our life, even in the first and second decade of life, but don’t cause cancer.

The earliest detectable abnormality is typically a polyp which is a tumour, a lump within the bowel which is detectable and if removed is almost certainly cured by removal alone but if it’s not detected then as that grows and acquires more alterations in genes then it can become a cancer and cancers develop the ability to invade the bowel wall, to spread to what we call lymph nodes or glands nearby and also to spread further afield, most commonly to the liver or to the lungs.  

And for most people whom bowel cancer has spread to the liver or to the lungs or elsewhere unfortunately we’re not able to cure their disease which as Claire has said is why there is such an importance in detecting cancers and pre-cancers as we call them so that the tumours are not actually cancerous but come before bowel cancer as early as possible. 

Helen: Thank you David. Moving on to the study, Ian perhaps you can take this, in the study that you carried out my understanding is that the whole genome sequencing was used to investigate the genetic changes that lead to the development and growth of bowel cancer. And for this participants with bowel cancer in the 100,000 Genomes Project donated both a blood sample and a tumour sample while those with rare conditions only provided a blood sample, can you explain why that is? 

Ian: As you said the study really looked at 2 quite separate arms albeit with a little bit of overlap as we’ll see. So, one very important aim was to look at individuals, both children and adults, who had medical problems or other conditions that were unexplained but which had some features that suggested that they weren’t necessarily inherited but there may be some variation in their genes that had caused them, and roughly half of the programme was dedicated to that.  

Within that there was a small number of people who had a strong family history of bowel cancer or who had large numbers of polyps in the bowel and they were analysed in a separate part of the project from what we’re mostly discussing. Within the cancer arm there was a collection really throughout England of patients who had most of the common types of cancer and a few with less common cancers.  

And because when we’re looking at genetic and related changes in cancers we need to make sure that those changes have actually occurred in the cancer as it started growing from its earliest stages with a small number of cells in the body that were slightly abnormal and then progressing. We need to look at what genetic variation the patient has in all the cells of their body. We don’t want to look at patients and say that looks an interesting change, we may be able to use that if it’s present in all of the normal cells in that patient’s system.  

We want to make sure the change is specific to the cancer itself and therefore we have to sequence both a sample probably taken from blood and a sample taken from the actual cancer. And in a way we subtract out the changes in the blood to identify the changes that have actually occurred in the cancer itself. 

Helen: That’s a very helpful explanation. Does this research show that there is a role for whole genome sequencing in clinical care? 

Ian: I think my own view is it is all a question of cost. I think the advantages it provides it can assess multiple types of genetic change at once. It is relatively consistent across each cancer’s genome between cancers, even between centres mean that it is the method of choice. There are undoubtedly developments that will happen in the future, maybe being able to sequence longer stretches of DNA in one go that will help the analysis.  

And some of the computational methods are likely to develop to identify some of the slightly difficult to identify genetic changes but it ought to be the standard of choice. There are issues and potential difficulties in collecting the high-quality samples that have been needed from pathology laboratory and that will be difficult going forward with current budges and there are lots of challenges but ultimately it in some form has to be the method of choice. What wasn’t done is to look at other molecule tests or essays, looking at RNA wasn’t really done on a big scale as well as DNA and other changes to DNA apart from the genetic changes were not looked at.  

So, there are certainly ways it could be improved if you had limitless money but I think the project, 100,000 Genomes has shown the whole genomes are. They have a lot of advantages and ultimately probably will be adopted by the NHS and similar organisations. 

Helen: David, could you now tell us about the findings of this pioneering study and what impact these findings might have on people with bowel cancer in the future? 

David: So, this is the largest study to date to analyse the entire genome of bowel cancer by some margin and the fact that we’ve done whole genome sequencing and in so many people it has really given us an unprecedented ability to identify the genetic alterations that drive bowel cancer. And within bowel cancer we’ve known for some time it is not a homogeneous entity that bowel cancer is not all created equal, that there are sub-groups of bowel cancer and we have been able to refine those over previous efforts. And I guess if you were to ask what the biggest take home for me from the study is it’s just the complexity of the disease.  

So, as we’ve mentioned we know that cancer is a genetic disease, that it’s driven by genetic alterations, alterations in genes which regulate the growth of cells or the death of cells or the spread of cells. And we’ve known for many years that there is a modest number of genes which are commonly malfunctioning in bowel cancer and they would be in the tens to dozens really. But with this work we’ve hugely extended our understanding of the genes that drive bowel cancer and in fact we’ve discovered nearly 250 genes which are altered in bowel cancer and appear to drive the growth of the cancer.  

Now we know that not all of those will be validated and by that I mean that there are associations that we find at the moment, not all of which will be biologically relevant but interpreted in the data we know a large number that are previously undiscovered are or we can be fairly confident of that. And one of the take homes from that is that many of these are only altered in a small fraction of bowel cancers.  

So, rather than being perhaps half of bowel cancers or a third of bowel cancers there are a good number of genes, a very substantial number of genes, which are altered in say 3 to even 1% of bowel cancers. And if we think about how we go about targeting those and perhaps we’ll come onto treatment later that poses really challenges for how we work and we would think about treating patients with bowel cancer who have those particular alterations in their cancers. 

Helen: Thank you David, yes we’ll come onto treatment shortly, but I think Claire has a question for you.  

Claire: Yes, thank you. For me as somebody who works in this every day this is such an exciting and interesting study, particularly in light of what we said earlier about early detection and how critically important that is for improving outcomes in people with bowel cancer. So, in your view do you think this research could help shape future screening programmes or prevention strategies? 

David: That’s a great question, I suppose in terms of screening at the moment the majority of screening is done in the UK at least by testing for blood in the stool which is relatively non-specific so I’m not sure that that would be directly impacted by this research. But one area of early cancer detection that is perhaps more relevant is quite a lot of work including from Oxford actually in recent years looking at blood tests. So, testing blood samples for early detection of cancer whereby you can test for genetic alterations, fragments of DNA that have alterations from the bowel cancer or any cancer that circulates in the blood and that tends to rely on a small number of common alterations.  

And with this data I could see that we might be able to refine those tests and in so doing improve our early detection of cancer but that would need quite some work before we could actually say look that had real potential I think. And in terms of prevention there are, I think Ian may want to come in on this, one or 2 sub-groups which you might think that you could try to prevent but of course that needs a lot of extra work really.  

But I think we have some clues of the biology of bowel cancer and particularly some of the sub-groups where you might think well this drug would work better in terms of preventing that sub-group or that sub-group but that will need to be the subject of future study. 

Helen: Ian, did you want to come in on that at all? 

Ian: So, at the moment prevention is a fairly new way of helping to reduce the number of people with bowel cancer at the level of the whole population which is what we have in the UK above a certain age group as we heard from Claire earlier. The methods used, again as we heard, are screening for occult blood in the stool and then colonoscopy to identify either hopefully early cancers or polyps and remove those. But when we think about the methods that we use for preventing other diseases then normally where they’re successful using a more easily delivered and I have to say less expensive method.  

So, high blood pressure is treated to reduce the risk of cardiovascular disease and there are other diseases where those what you might call molecularly-based prevented strategies are coming in. We really lack that for bowel cancer in particular, it does happen for some other cancers, but one of the great hopes is that some of these new genes that we’ve found could be useful in preventing cancer. And it doesn’t necessarily matter that they’re rare, even if there are only 1% of cancers, by using those and changing those in a normal individual before they have had cancer then we may be able to reduce that risk.  

So, there are lots of potential new targets for prevention that are coming through and as David said it is going to take a lot of work to work out which of those are deliverable and who will benefit. But we have quite a lot of opportunities in that space and although that may not be us that takes that forward, it may be, but it may not be. We think it is a lot of material for those interested in chemo prevention using drugs of cancer that they can work on and with luck deliver some new ways of preventing cancer that may be simply popping a pill every morning to take your risk right down to as close as zero as we can. 

Helen: Thank you Ian. David, I think you had something to add here. 

David: Thanks Helen. One area of prevention that we’re really interested in Oxford and many others are is using the genetic alterations that we find in bowel cancers and other cancers as targets for vaccination. Now we know that gene alterations will cause abnormal proteins which while they might drive the cancer, make it grow or not die, can also be recognised by the immune system so the abnormal proteins can be recognised by the immune system as being foreign and as foreign they can be targeted by the immune system so the immune system will try and kill the cells carrying those alterations. And we know for some sub-sets of bowel cancers those alterations can be relatively predictable actually, they occur in quite a sizeable fraction of some sub-groups of bowel cancers.  

And one area that we’re particularly interested in at the moment and actively pursuing is using those targets where you need some additional work to demonstrate when they are particularly recognisable by the immune system. But to use these genetic alterations is potential targets for vaccination with the intention ultimately of preventing bowel cancer in at risk individuals or ideally in the full-term time the whole population. And we’ve received some funding from Cancer Research UK to pursue this line of research and we have a group working on this in Oxford and as I say many others do elsewhere. 

Helen: Thank you David, yes I have a vested interest in this because my understanding is this work is aimed primarily at people with a genetic condition called lynch syndrome which predisposes the people who have inherited this gene change alteration to bowel cancer, womb cancer and other cancer. And I had womb cancer, as I think David you know, a few years back and discovered it was due to lynch syndrome and so it’s really exciting that you’re now looking at vaccinating preventing because yes I take aspirin every day, I have my colonoscopy every 2 years which have some effect on preventing these cancers but it’s not 100% guaranteed. And I don’t suppose it ever will be but having the vaccination in that armoury would be fantastic I think for future generations, it’s very exciting and we look forward to hearing more about it.  

Thank you Ian and David. I mean we’ve heard a lot there about preventing bowel cancer but I think moving back now to potential treatments, you know, we’ve heard from David how this study has shown a number of actionable findings but what are the next steps towards treatment? How can these findings be turned into real actions that will benefit those people diagnosed with bowel cancer in the future? Ian, perhaps you would like to pick up on this to start. 

Ian: That step is one, you know, in which I’m not personally an expert but a lot of the newer treatments are based on the finding of so called driving mutations which are simply genetic changes that occur as the cancer grows and contribute to that growth and ultimately if it’s not treated to the spread and dissemination of a cancer. And the fact that we have reported 250 which need validation but of which a large proportion are likely to be true drivers means that anyone of those can be a potential new target.  

The criteria to be used for which of those mutations to pursue, which of those driver genes to chase up are quite complicated normally, depend on many things such as the interest of research groups and small and larger drug companies. And the similarity of those genes to other genes that have evolved and the processes that they make to go slightly wrong in the cancer.  

So, there is also the issue that because these are uncommon, everybody talks a lot about personalised medicine or precision medicine, this would be truly precision or personalised medicine because a genetic change that was driving the cancer in only 1% of patients is obviously not a huge number of patients although bowel cancer is a common cancer so it’s not a tiny number either. But it would mean investment at that level to benefit let’s say 1 to 2% potentially of all patients with bowel cancer but I think that’s a nettle we have to grasp. And I think our results are showing that most of the really common drug changes either have not yet been successfully targeted in treatment or are too difficult to target.  

So, we’re going to have to start looking at these less common genetic drivers and design strategies, inhibitors, you know, again that can be delivered to patients relatively straightforwardly in order to see whether they benefit the patients concerned. But there is this problem of getting enough patients enrolled in clinical trials where a change is only present in a relatively small proportion of all the patients with that cancer type.  

Helen: Thank you Ian. Presumably if there is a relatively small number of patients the people who are looking at running these trials might be looking at perhaps international trials, would that be one way to go? 

Ian: So, I think David can speak with more personal knowledge but there are international trial networks and there are collaborations along these lines already under way. I would hope that those could be made use of even more than they are already. There is, you know, a financial consideration for those developing new anticancer treatments which are, you know, high risk work and also the costs of setting up trials and enrolling people is not a trivial thing. So, I think those are hurdles that can be overcome but it would need a concerted effort to do that. Patients will play a major role in that and patient organisations as well as 100,00 Genomes and other similar projects. 

Helen: Yes, thank you, David I don’t know if you want to come in on that. 

David: Yes, the challenge of testing therapies in small groups is a very real one and there is lots of interest at the moment in exploring alternatives to conventional clinical trials. And as we use more electronic patient records and we have pharmacy records so there is the potential to get those data from routine clinical practice and there is lots of investments and attention on that at the moment so called real world data which is always an interesting term as if patients in clinical trials aren’t in the real world which of course they are.  

But it’s perhaps a little more cost effective sometimes in clinical trials, of course it does pose its own challenges in how you disentangle true treatment effect from other factors because there are many factors impacting on how long people with cancer live. But there is a lot of investment and effort going into that at the moment and it will be interesting to see how that develops over the coming years. 

Helen: Turning to you Claire based on your experience how well do you think people with bowel cancer understand how genomes can help with their care and what support is currently available to them in this area? 

Claire: I think the answer, as it is so often is, it’s dependent on individuals and not just one individual. So, I think some patients are very motivated to know as much about this as possible and to understand and to know what the next steps may be in their own treatment that may be helped by this. Others don’t want to have the same knowledge and want to be guided very much by their medical teams but I think oncologists obviously are at the forefront of this and we see at the charity … we have services at the charity that supports patients and we see lots of queries into our ask the nurse service where people have been given variable information about I suppose personalised medicine as Ian alluded to and how their very specific bowel cancer may be treated, so I think it varies from patient to patient.  

There is support available so we have the ask the nurse service I alluded to. We have a brilliant patient forum actually and everybody in clinical practice will have seen this, patients often become more expert than anybody and they share advice and they’re moderated forums that are a very safe place for people to ask questions where there is a moderator to ensure that it is made really clear that circumstances are individual.  

And the same with the ask the nurse service because you don’t have all the clinical information so it is about empowering people, so there is support available. I think the other thing that is really important is equipping specialist nurses with the knowledge that they need to support their patients. This is a really exciting area of evolution for bowel cancer particularly I think in all cancers at the moment but for bowel cancer I think things have changed fairly rapidly in recent years and specialist nurses really need support in knowing that they have up-to-date information to give their patients.  

So, that’s another challenge for us and any specialist nurses that might be listening to this podcast we have online education on genomics for specialist nurses. Just while we’re talking about that and you mentioned lynch syndrome earlier, so there has been a lynch syndrome project as I’m sure you’re aware where we’re trying to get testing for lynch syndrome brought into local hospitals.  

So, there was some funding via NHS England so that the testing be done at time of diagnosis, so a pre-test and then a final test if that’s appropriate, for everybody diagnosed with bowel cancer to see if they have lynch syndrome. And in some trusts that has been done and in others it hasn’t yet and the funding hasn’t quite followed in the way that we need it to enable that to happen. It’s vitally important, we think there are about 175,000 people in the UK with lynch syndrome and we only know about 5% of them. And this is a gene change that is an inherited gene change so we can do what we call cascade testing where we test family members and we can then employ preventative strategies to prevent people from developing bowel cancer.  

So, it’s a really important project, so I think as well as supporting patients with the information around the changes that are happening in this area we also need to ensure that we support the workforce and have investment there to enable the support of all the changes and the genomic landscape. 

Helen: Absolutely Claire and so much resonates there with what you’ve said. Having myself had cancer discovered that was due to lynch syndrome, cascade testing offered to my family members so valuable. It turns out I inherited my change from my mum who is 83, has never had cancer, so I think that’s a very good example of, you know, it doesn’t necessarily mean that you will get cancer but actually on that point that you made about empowering patients I always have a right smile because there is my mum going off to all her other medical appointments because at 83 she sees quite a few people and she is always the one telling them about lynch syndrome and educating them because most of them haven’t heard of it, so yes it’s really, really important.  

And that patient forum, you’re probably aware of Lynch Syndrome UK, I don’t have any involvement in that other than being a member but that is so valuable for people with a particular condition to go somewhere where they can talk to or listen to other people with a similar condition, really, really valuable.  

Right, well I think circling back really to the 100,000 Genomes Project I think you touched on this earlier David but reflecting on what you and Ian have told us about your study what is it about the 100,000 Genomes Project bowel cancer dataset that made this work possible? 

David: There are a few things, one of which and not least of which is the sheer size of the effort. So, to have whole genome sequencing for more than 2,000 individuals is previously unprecedented and we’ll be seeing more of this now as we scale up our research efforts but at the inception of the project it was very, very ambitious and to be able to deliver that is a huge achievement. And the quality and breadth of the analysis is very strong as well.  

And ultimately, you know, the former gives thanks to the people that were kind enough to donate samples to the 100,000 Genomes Project, they did so knowing that they almost certainly wouldn’t benefit personally from their donation from their gift and that any benefits would be some way down the line and hopefully benefit others which is what we’re seeking to realise now. But, you know, it’s not a given when we treat people in the clinic so we’re very, very grateful to those individuals.  

And I think also to the scientists who worked incredibly hard over the last 5 years to deliver this work actually. So, having been part of the team and being lucky enough to be part of the team along with Ian we’ve had hugely motivated individuals that really have dedicated a large fraction of their working lives to delivering this project which I think is a fantastic achievement as well. 

Helen: Thank you, thank you to all those participants who at a time when their lives probably were turned completely upside down by a cancer diagnosis were offered the chance to join the 100,000 Genomes Project and said yes. As you say most of them will have known that it won’t have helped them but by donating their data, you know, it has allowed this work to happen and potentially it could change lots of people’s lives in the future, so thank you to them. 

Ian: Could I also just emphasise and agree with what David has said, I won’t go through all the individuals by name, but if anybody wants to read the published report of the work there are several people on there, Alex Cornish is the first author, but many colleagues from an institute of Cancer Research, The University of Manchester, Birmingham, Leeds, other universities in London that all contributed, but also colleagues in the NHS and/or universities who recruited patients, collected samples, processed them etc and of course the people who did the preparation of the samples in genetics laboratories and actually did the sequencing and basic analysis too.  

So, it is a truly huge effort across particularly all the cancer types which is particularly a complex collection given the fact the tumour is needed and a blood sample. It’s quite difficult in a way to find a formal way of thanking them for all of this but without them it wouldn’t have happened. 

Helen: On that note I think we’ll wrap up there. A huge thank you to our guests, Professor Ian Tomlinson, Clare Coughlan and Dr David Church for an enlightening discussion on the groundbreaking study published in nature. This research is set to reshape our understanding of colorectal cancer and pave the way for new possibilities in treatment and patient care.  

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

In this explainer episode, we’ve asked Adrianto Wirawan, Director of Bioinformatics Engineering at Genomics England, to explain what the term 'no primary findings' means.

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 [email protected].

You can download the transcript or read it below.

Florence: What does ‘no primary findings’ mean? I'm joined by Adrianto Wirawan, Director of Bioinformatics Engineering for Genomics England, to find out more. So firstly, Adrianto, when we speak about findings from genomic tests, what does this mean? What are we looking for when we do a genomic test? 

Adrianto: Our DNA is made up of a long sequence of letters that act like instructions for your body. 

Genomic testing analyses these letters to see if there are any unusual patterns or changes that might change your health. You can imagine your DNA as a book full of recipes for your body. Every recipe tells your body how to make proteins that keep you healthy, and sometimes there might be a typo in the recipe, like missing an ingredient or mixing up the steps. This could result in a health problem, just like how a changed recipe can lead to a bad dish. 

On average, we would expect about 5 million out of our 3 billion DNA letters to be different. And each of these, we call them a genetic variant. Genomic testing is designed to examine some of these variants to help inform our healthcare. So, for example, in understanding why certain health problems happen and in choosing the best treatment based on our unique genetic makeup. 

Florence: And what do we mean by primary findings? 

Adrianto: Primary findings mean that in a patient's genomic testing, we identified a set of variants that is linked to the patient's condition. The variants that we have makes us who we are. However, not all of them cause a disease or contribute to a health problem. our bioinformatics pipelines will automatically prioritise variants of potential relevance to the patient's conditions. Using this data, the NHS clinical scientists will then determine whether any of these prioritised variants are linked to the patient's condition and whether a genetic diagnosis has been identified, which would explain why certain health problems happen. 

Florence: So, then what happens when there are no primary findings?  

Adrianto: When no primary findings are found, that means that no genetic diagnosis has been identified. As developments are made and our knowledge of the variance improves over time, additional findings might be identified in the future. 

The clinical team responsible for a patient's care may request reanalysis of data according to the national guidance, following a change in the patient's clinical status to inform reproductive decisions, or after significant new disease gene associations have emerged. 

In addition, Genomics England also provides the diagnostic discovery pathway where we focus on uncovering new diagnosis, where the participants of the 100,000 Genomes Project, as well as the patient's sequenced through the NHS Genomic Medicine Service  

This is meant to be more equitable as we don't rely on the clinical teams to raise individual separate requests. 

Florence: And finally, what do we mean by secondary findings?  

Adrianto: Secondary findings are additional findings not related to the conditions in which the patient was recruited for. For example, if a patient was recruited for one type of cancer, but perhaps we found variants linked to a different condition. We explored secondary findings for the 100,000 Genomes Project but we do not do secondary findings for the Genomic Medicine Service.  

Florence: That was Adrianto Wirawan explaining what we mean by ‘no primary findings’. 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. 

In this explainer episode, we’ve asked Mathilde Leblond, Senior Design Researcher for the Generation Study at Genomics England, to answer some frequently asked questions that we received from parents who we engaged with for the design of the study.

You can hear more information about Generation Study via the study's official website and in our previous podcast episodes:

• How has design research shaped the Generation Study?

You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel.

If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on [email protected].

You can download the transcript or read it below.

Naimah: You may have heard about the Generation Study. This research study led by Genomics England in partnership with NHS England will sequence the whole genomes of a hundred thousand newborn babies and will look for more than 200 rare conditions that could be treated in the NHS in early childhood. 

The study seeks to improve how we diagnose and treat rare genetic conditions to enable babies and families to have better outcomes. Today I'm joined by Mathilde Leblond, who leads design research for the Generation Study, and will be answering some of the frequently asked questions that we receive from parents who we engaged with for the design of the study — the same questions that expectant parents at participating hospitals might have before deciding if they want to take part. 

So first of all, Mathilde, can you tell me a little bit more about your role? 

Mathilde: Hello. So, I'm a design researcher. My role is to support my colleagues, understand our users deeply so that we can create experiences that are as positive and seamless as possible. 

So today we'll talk about the parents who are the ones invited to take part in the Generation Study, but our users also include the midwives who are approaching them and taking blood samples. The clinical scientists who are interpreting the results and the specialist paediatricians will be contacting the parents if a condition is suspected, and even many more users actually. 

So, we did a lot of research prior to launching to shape the Generation Study, and now that we're live, we continue doing more to keep improving the experience. 

Naimah: Okay, so can you give us a bit of background? How did you engage with parents in this study? 

Mathilde: Yeah, so today we've involved over 150 pregnant and recent parents in our co-design sessions. 

And these sessions were slightly different each time with different topics and exercises, but generally we spend around 90 minutes with one parent. And we asked them to bring someone who helped them make decisions about their baby during their pregnancy. So that meant that we had their mums, their sisters, their husbands, their wives and friends as well, taking part and discussing the Generation Study with us. 

During that time with them, we would test our materials. We listened out to what's important to them and what they asked about, and we got them to show us what would work better for them so that we could then shape the materials around that.  

Naimah: So you can find out a bit more about why it's important to involve users in co-design in our podcast ‘How has design research helped shape the Generation Study?’, which is available on our website.  

So, we have a list of frequently asked questions from some of the parents, and I wanted to post some of them to you today, Mathilde. So first of all, one of the questions was, why should my baby take part in this study? 

Mathilde: Yeah, I mean, that's really the key questions that all parents are asking themselves before they even spend any time finding out more about the Generation Study. And our materials do reflect that. So what tends to matter most to the parents we spoke to, is that there's a small chance that their baby may benefit directly from taking part because if a condition is suspected, they'll be invited for further specialised tests within the NHS, and they could receive treatment much sooner than if we had waited for the symptoms to develop and for a diagnosis to come, which can sometimes take years for some rare conditions. But for a large majority of the babies, 99%, they will have no condition suspected and so their involvement really is more altruistic. Taking part means that their parents agree to share the baby's healthcare records on an ongoing basis and their genome with researchers who can then look at this together with information from thousands of other babies and patients to help improve our understanding of genes and health. 

So taking part in the Generation Study also means that you might help uncover some life-changing early treatments for babies in the future. And finally, something that's super important to us is that people from Black, Asian and other minority ethnic communities have historically been underrepresented in this type of research. So, we're working hard to make the Generation Study as inclusive as possible to help genetic testing and treatments be improved for everybody in the future. So, there's many reasons to take part in the Generation Study.  

Naimah: You mentioned the word altruistic there. Can you tell me what that means?  

Mathilde: Yeah, so that's really to help society. They may not get benefits within their own lives or within their own family, but somebody somewhere will benefit from it in the future. And that's what altruistic means.  

Naimah: Thank you. So, some parents might also ask, will this test tell me every illness that my baby might have now and in the future? 

Mathilde: No. So first of all, we're still learning a lot about how genes work, how the environment affects them, and there's also many conditions that we still don't understand very well. So those are not in. Of the conditions that we do understand quite well. We did a big piece of public engagement in 2022 to try and decide which ones to include as part of the screening. 

And while some parents told us that they would want to know every single thing in advance, a lot of parents were worried about how much it would raise their anxiety to find out about a potentially incurable condition at such a fragile and beautiful moment when you have a new baby. So, for this reason and many other reasons, we've decided to proceed really cautiously so that the conditions that we'll be testing for have been chosen to reflect 4 key principles. And you can find them on the website. But the main gist is that we'll only be looking for conditions that normally start in childhood, first few years of life. So, nothing around Alzheimer’s, nothing around breast cancer, for instance. And another principle is that there's has to be already existing pathways within the NHS so that the babies can be seen and treated quickly. So, we're only including those conditions that start in childhood, and something can be done about them early on. 

Naimah: You can also listen to our podcast on our website 'Which conditions will we look for initially in the Generation study?’ to find out more about the list of 200 conditions, which we'll look for in the study and how this may change over the course of time as new evidence emerges. 

So, another common theme with the parents was that they are aware that the NHS is already under a lot of pressure, and they asked if my baby is flagged for more testing, will I really be able to get the support I need from the NHS in time?  

Mathilde: Yeah, that's a question that we've heard a lot actually, and it really makes sense considering the media coverage that's coming out daily, and that's been really in the papers for months now about how stretched the NHS is. 

We've worked really closely with the NHS to ensure that all the babies that have a condition suspected as part of the Generation Study can be seen as soon as possible. So, our team has been in touch with specialists from across the country to understand how ready they are to take in those babies, to run confirmatory tests and potentially start treating them sooner. 

So, it's been really key for us to make sure that we're not flagging up a baby for more testing and they just have to wait for months before they can get extra tests and attention. And that's so important for us to get right. In the long term, we hope that screening could actually relieve some pressure from the NHS if we can get babies to the correct doctor earlier on while their health is still good. 

Naimah: Some parents might also ask, this research sounds very new. Is my baby going to be a Guinea pig?  

Mathilde: Those two words, Guinea pig, came up again and again in almost every single session that I've had with parents, it was almost a freaky coincidence. I find that most parents use this wording to mean, will we inject anything into their baby or give them any medication that has not been tested and approved? 

And the answer to this is no. What does happen is that when a baby's born after the birth, we need to take a few drops of blood so that we can create their genome, their DNA, and normally we'll take a bit from their umbilical cords, and that is happening in most of the birth at the moment of the participants. 

But if for any reason we couldn't take that, maybe it was a complex labour, there was some emergency. The parents are asked a bit later if they would allow for a bit of blood to be collected using the heel prick methods. And that's a method that's been used in the babies in the UK within 5 days of birth for many, many years. And it looks for 9 conditions, as a current NHS test. So that's definitely safe. And usually when parents find out that that's all there is to it, they feel a lot more comfortable. A little disclaimer here because we mentioned the 5-day heel prick, while we use a similar method to get the blood, if we couldn't get blood from the umbilical cords, it's important to see that this is a different test, it's a proven test within the NHS which says many lives. So, parents who choose to take part in the Generation Study are very much encouraged to also agree to the day 5 newborn screen screening.  

With all of that being said, this is a new research study and there are some uncertainties. Most of them revolve around how quickly we can process the results, how will parents and the NHS react to receiving these results so early, but also will this be inclusive for everybody? And might we inadvertently create more inequities? We're actively listening to sites now that we have opened and we have a survey that our participants can fill out, and we're working with UCL to help evaluate the impact of the Generation Study in an unbiased way. 

Naimah: Okay. And another frequently asked question, if you have my baby's DNA, does that mean that you can clone them?  

Mathilde: Cloning comes up regularly in our interviews with parents, though sometimes I found that people can feel a little bit silly asking about it, but actually it's a quite big topic that's top of mind when we talk about DNA and genomes. 

Not least because of how much it comes up in sci-fi, it's just everywhere. So first of all, about cloning, it's important to remember that it's completely illegal, but it also has a whole host of other ethical concerns, which we don't take lightly at all here at Genomics England. So, the research that our study will support will be firmly within the bands of law and ethics and will only focus on discovering answers to questions that could help the health and wellbeing of babies, and really all of us in the future. No cloning involved. 

Naimah: Okay. And then the final question, how can I take part in the study? 

Mathilde: We've already opened in over 10 hospitals in England, which we are very excited about and we're actively working on opening more. You can visit our website, www.generationstudy.co.uk, to see an up-to-date list of hospitals which are currently taking part, and to read more about what taking part entails. Then you can contact your local research team to log your interest if you're planning on giving birth in one of our partner hospitals, and they'll be in touch to let you know about the next steps. 

Naimah: That was Mathilde Leblond answering some of the frequently asked questions from parents that we have engaged with for this study. If you've got any questions or you'd like to hear more, please contact us at [email protected], or you could find out more on the Generation Study website www.generationstudy.co.uk. 

Thank you for listening.

In this explainer episode, we’ve asked Callum Morris, Pharmaceutical Research and Development Insights Manager at Genomics England, to explain what happens in a clinical trial.

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 [email protected].

You can download the transcript or read it below.

Florence: What happens in a clinical trial? I'm joined with Callum Morris, Pharmaceutical Research and Development Insights Manager for Genomics England, to find out more. So, Callum, first things first. What is a clinical trial?  

Callum: So, a clinical trial is a study that looks to people to answer a specific medical research question. 

So, this involves gathering a group of participants that are willing to participate in providing evidence on how to improve clinical care. And so, the main purpose for a clinical trial is to evaluate health related outcomes between different groups of participants. If it's an interventional clinical trial, you change clinical care for one group and not another. 

And evaluate whether the change you made improved health outcomes for that group, or if it's an observational clinical trial, you might focus on different groups but not change anything about their clinical care and collect real world data to understand how outcomes differ across the groups. 

Florence: Can you briefly explain what we mean by real world data?  

Callum: Sure. So real world data relates to data collected routinely as part of standard clinical care. So, it could be collected from your electronic health records, data from product or disease registries, or data gathered from other sources such as digital health technologies. 

And all of this can inform on particular groups from the population you're interested in. 

Florence: And are there different types of clinical trials?  

Callum: Yes. Clinical trials can take many forms depending on the medical research question you're trying to answer. They could be related to understanding the risk of disease. So, evaluating a potential risk factor that you may be concerned with. They might evaluate preventing disease. So, what different approaches can you take to people who have never had the disease, and does this prevent its occurrence? You can have a clinical trial that looks at screening for disease. For cancer, that's really important. 

Does a new screening approach mean more people with cancer can be identified earlier? And importantly, does this lead to an improvement in survival? You can have clinical trials that evaluate the different approaches to diagnosing a disease and can you diagnose a patient earlier and better? 

And then the classical clinical trial is revolving therapeutics or different treatments, and you can have treatments that are addressing the disease itself. Or you'd have treatments that are controlling the symptoms of side effects you might get from another treatment you might be taking.  

So even within a specific medical research question, you can have different clinical trials depending on how much evidence you already have regarding that question. For clinical trials involving the assessment of new treatments and therapies, these are broken down into three stages and we call these phases. 

So, you have phase one, phase 2, and phase 3. 

Florence: Can you explain a bit more about these phases?  

Callum: Sure. So, the overarching medical research question might be, what is the safety profile of this new therapy, and does it work improving on the current standard of care? So, you'll break this down depending on the phase, and with each phase you expand your clinical trial to a larger population. 

Phase ones are typically on a small group of people around, let's say 20 to 50, and are designed to check the safety of a new drug that's being entered into humans for the first time. Sometimes, especially in early phase cancer trials, you're trying to find the right dose for your patients. 

So, you might take a small group, test them on a low dose, and if there are no severe reactions to the new drug, you start incrementally increasing your dose a little bit more. And this gives you a really good idea of the safety profile of your drug as you try it for the first time in a human population. 

Next, you'll move on to a phase 2. And these are typically larger than your phase one, around 50 to 200 people. And, usually you use the dose recommended by the phase one. So instead of slowly adjusting your dose and just focusing on the drug safety profile, the phase 2 will evaluate the safety of the medicine in a large population, but also have an additional focus on health-related outcomes. 

Is the medicine causing the effect you want? Whether that's relief of symptoms or for cancer reduction in the size of your cancer. If the data is really promising from your phase two, it will move to a phase 3. And the idea is the same, increasing the size of the population. typically phase threes can be from 300 to 3000 participants. 

And the key thing here is that you will evaluate the potential benefit of your new treatment against the current standard of care. Normally, meaning the treatments that are already available in the clinic. Health regulators will need to look at all the data collected from all the trials before they approve it for the general population. 

And typically, they need a phase 3 to do this. They need a phase 3 to confirm that the benefit provided by the treatment outweighs the potential risks associated with it, across a fairly large cohort of participants. And this is to ensure the therapy is appropriate to be given to the general patient population. 

But also, a phase 3 is needed to see that if the new treatment is moving clinical care forward in the right direction and in providing improvements for patients against what is already available in the clinic. And this is the process by which we call it evidence-based changes, to make improvements to clinical care. 

Florence: So then how do people join clinical trials? 

Callum: So firstly, it's about becoming aware of the clinical trial. You might be referred to a clinical trial by your doctor who's been aware of it and where it is. Or you might be able to find a clinical trial using clinical trial databases or finding about them through patient advocacy groups. 

And they should be able to tell you which hospitals are taking part in the clinical trial. So, the next step might be your doctor can contact someone on the research team, and there is always a principal investigator per research site that is always a medical professional. 

The study team at the site have all undergone training from the people organising the trial to run through the protocols necessary to keep the trial consistent in different sites. 

Once they've been contacted, you'll undergo a screening process, and what they'll determine is your eligibility for the trial. They might assess medical history or your health status. And if you're eligible for the trial, the next step is to provide informed consent. The healthcare team should provide detailed information about the trial, its risks and benefits, the aim of the trial, and who's funding it. 

And what are the treatment options for participating and not participating in the trial? How long is the follow-up in the clinical trial? And what will happen if you leave the clinical trial? And then also what are the safety concerns for the clinical trials and the possible side effects if it's something to do with a new treatment. Once you've been informed of all these details and you agree to be part of the clinical trial, you'll sign a consent form, and that means you're officially enrolled in the clinical trial. 

Florence: And what happens once someone is enrolled in a clinical trial?  

Callum: Once you are in the trial, you'll follow the procedures outlined in the trial protocol. This can take many forms, but normally it involves more regular follow-ups and check-ins with the clinical care team. And this is to establish safety concerns and to enable lots of data collection. 

There also may be additional checks related to health outcomes during the trial, and so the study team may want to take additional samples to understand what is happening physiologically during the study. There also may be additional questionnaires for you to fill out, to capture patient reported health outcomes. 

And this is to understand the patient's quality of life whilst they're on the trial. So, depending on the protocol, you may be followed up for a set period of time, and that may get less frequent as time goes on. And of course, you may pull out of the trial at any point after which the follow up will stop. 

So, following data collection, there may be a while before you see anything, but results should be published following analysis of the data.  

Florence: And finally, why might someone want to be involved in a clinical trial?  

Callum: Clinical trials are all about providing evidence to improve clinical care. At any time we want to make a change to healthcare, we want it to be evidence-based. And so, this requires lots of people all contributing in a group effort to generate a data set large enough to determine how to change our approach to healthcare and move the field forward for improving people's lives. 

Florence: That was Callum Morris explaining what happens in a clinical trial. If you'd like to hear more explainer episodes like this, you can find them on our website www.genomicsengland.co.uk. Thank you for listening. 

In this explainer episode, we’ve asked Nicole Chai, Research and Development Bioinformatician at Genomics England, to explain what X-linked inheritance is.

You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel.

If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on [email protected].

You can download the transcript or read it below.

Florence: How does X-linked inheritance work? I'm joined by Nicole Chai, Research and Development Bioinformatician for Genomics England, to find out more. So firstly, Nicole, can you explain a bit about the X and Y chromosomes?  

Nicole: Sure. So, the X and Y chromosomes are what we call sex chromosomes. And chromosomes are packages of DNA in our cells that are inherited from our parents, and they contain information about our physical and biological traits. 

Some examples of traits that are determined by our chromosomes include what colour our hair is and what colour our eyes are. And each of these individual traits are determined by smaller sections on the chromosome called genes. Genes can also determine what medical conditions we may inherit from our parents. 

As humans, we all typically have 23 pairs of chromosomes in each of our cells. One of these pairs consists of the sex chromosomes, and as their name suggests, sex chromosomes determine sex of an individual. And typically, females will have two X chromosomes and males will have one X and one Y chromosome. 

Florence: So then, what do we mean by the term X-linked condition? 

Nicole: So, an X-linked condition means that the condition is associated with genetic changes on the X chromosome. And what we mean when we say genetic changes are changes to the normal sequence of DNA on the gene. And this can sometimes lead to medical disorders. 

Florence: Do you have a specific example of an X-linked condition?  

Nicole: Sure. So, an example of an X-linked condition is Duchenne muscular dystrophy. 

And with this condition you get a progressive loss of muscle due to the lack of a protein known as dystrophin. Another example of an X-linked condition is red-green colour blindness. And this is where people affected with the condition can't see shades of red and green the way most people see them.  

Florence: Could you explain how X-linked conditions are inherited?  

Nicole: Sure. So, for many conditions, there are two ways they can be inherited, either dominantly or recessively. Dominant inheritance is usually when you just need one copy of the gene to be affected by the condition, whereas recessive inheritance is when you need two copies of the gene to be affected by the condition. 

However, this works slightly differently with X-linked conditions, and most X-linked conditions are inherited recessively. 

Florence: So why does inheritance work differently for X-linked conditions? 

Nicole: So the reason that inheritance works differently for X-linked conditions is down to the differences between sex chromosomes, between females and males. As females have two X chromosomes and males have X and Y, this means that for recessive excellent conditions, males only need one altered gene to have the condition. 

So, because males only have one X chromosome, if they inherit a faulty copy of a recessive gene, they don't have another healthy copy to compensate. 

On the other hand, as females have two X chromosomes, if they inherit just one faulty copy, they do have a healthy one that can compensate for that one. So as a result, what we tend to see is that males are more commonly affected by X-linked recessive conditions. 

Florence: That was Nicole Chai explaining the term X-linked inheritance. If you'd like to hear more explainer episodes like this, you can find them on our website www.genomicsengland.co.uk. Thank you for listening. 

In this explainer episode, we’ve asked Arina Puzriakova, Scientific Curator at Genomics England, to explain what a polygenic disorder is.

You can also find a series of short videos explaining some of the common terms you might encounter about genomics on our YouTube channel.

If you’ve got any questions, or have any other topics you’d like us to explain, feel free to contact us on [email protected].

You can download the transcript or read it below.

Florence: What is a polygenic disorder? I'm joined by Arina Puzriakova, Scientific Curator for Genomics England to find out more. So, Arina, first things first. How can our genes affect our health?  

Arina: So, genes are short sections of DNA that contain information that the cells in your body need in order to make proteins. Each gene carries the instructions for making a specific protein, and each protein performs a different task that allows the body to develop and function properly, depending on the genes that we inherit from our parents. Also determines our unique physical features such as our eye colour, hair colour, and height. 

When a gene contains a change that disrupts the gene's instructions, also known as a gene variant, in some cases, this can lead to the production of a defective protein or prevents a protein from being made altogether. A missing protein or one that is not working properly can have a knock-on effect on how the body functions and this can result in health issues or the development of a genetic disorder. 

Florence: So then how can a gene variant lead to a disorder?  

Arina: So the genetics of each disorder are unique. In some cases, a change in a single gene is enough to cause a genetic disorder, and these are known as monogenic disorders. These conditions often occur in childhood and tend to cause severe illness. individually, they are more rare affecting a smaller number of people in the population, and usually they run in families as parents pass the damaging variance onto their children. 

But these changes can also happen spontaneously without a known cause. An example of a monogenic disorder, which some may be familiar with, is cystic fibrosis. Cystic fibrosis affects one in every 2,500 babies born in the UK, meaning that there's about 11,000 people living with cystic fibrosis. 

Florence: So, we've just talked through monogenic disorders. What do we mean by polygenic disorder?  

Arina: So polygenic disorders are on the other end of the spectrum for disorders. 

They are caused by the combined effects of multiple different genes. Individually, each gene has a very small effect on causing the disease, but many variations in different genes can act together to have a great impact on individual's susceptibility to that condition. Environmental and behavioural factors such as your lifestyle and diet also often have an effect. 

Polygenic disorders are much more common, typically affecting millions of people in the population, and they're usually diagnosed in adulthood.  

Florence: Could you give me an example of a polygenic disorder?  

Arina: A common example of a polygenic disorder is type two diabetes. It affects almost 4 million people in the UK. 

So this means that we know there are many genetic variants that could have made these individuals more susceptible to diabetes, but there are also other factors such as age or being overweight that could have increased their risk. 

Florence: Are there specific challenges when it comes to diagnosing or treating polygenic disorders? 

Arina: So, if I start with monogenic disorders, these are much easier to test for because we simply need to look for the presence or the absence of a faulty gene in order to determine whether someone is a carrier of a genetic disorder. On the other hand, testing for a polygenic disorder is a lot more complex as they are influenced by the combined effects of many genes. 

Meaning there is no single genetic test or treatment that will work for all patients with the same condition. We need large and diverse groups of patients to study in order to accurately determine which genes are important and which ones are not. 

And this can be challenging to obtain. Also accurately measuring and comparing lifetime environmental factors and exposures further complicates the assessment. 

Another challenge with polygenic disorders is that even though they can cluster in families, the inheritance is not as clear cut or predictable as it is with monogenic disorders. Carrying a specific combination of genetic variants that are already known to be associated with polygenic disorder does not necessarily mean that you will definitely develop that disorder. 

However, this information can be used to calculate something known as a polygenic risk score, and this provides an estimate for the risk of developing polygenic disease at some point in life based on individual's unique genetic profile. 

Florence: And why can knowing apologetic risk score be helpful? 

Arina: So, by being informed about the probability of developing a particular polygenic disease, an individual can make behaviour or lifestyles changes that could help reduce their risk. To go back to the previous example, somebody who is more likely to develop type two diabetes based on their genetic makeup can do things like maintain a healthy weight. And eat a healthy diet to help reduce their risk of developing type two diabetes in the future. 

Florence: That was Arina Puzriakova explaining what we mean by polygenic disorder. 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. 

The Generation Study is a research initiative aiming to explore the use of whole genome sequencing in newborns, to screen for more than 200 rare genetic conditions. This study will recruit 100,000 babies across England, and you can learn more about the Generation Study via the study's official website.

Design research has played a vital role in shaping the Generation Study. Parents, NHS staff, and the public have been involved from the start, providing input through public dialogues and usability testing to guide the development of the study.

In this episode, our guests discuss the use of design research in the Generation Study, and the importance of designing a robust and inclusive consent process, focusing on building trust and engaging diverse communities. They also discuss how the design of study materials such as posters, videos, and written content was shaped by community feedback.

Our host, Öznur Özkurt, Director of design and research at Genomics England is joined by Mathilde Leblond, Senior Design Researcher at Genomics England, Rebecca Middleton, a rare condition patient, and Chair of the recruitment working group of the Generation Study and Sandra Igwe, CEO/founder of The Motherhood Group.

"It’s not enough to just ask people afterwards. It’s also not enough to engage just at the beginning and then stop listening once we’re live, once it gets hairy and a bit difficult. So, we are very excited to find out all the things that we hadn’t considered before we launched, and just continue to learn."

You can hear more information about Generation Study in our previous podcast episodes too:

You can download the transcript or read it below.

Öznur: Welcome to Behind the Genes. 

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

Öznur: My name’s Öznur Özkurt and I’m the director of design and research at Genomics England. On today’s episode, I’m joined by Mathilde Leblonde, senior design researcher at Genomics England, Rebecca Middleton, and Sandra Igwe, CEO and founder of the Motherhood Group. Today we’ll be discussing how design research was used in the Generation Study by involving participant and users’ voices to address ethical considerations, implementation and consent. 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, before we dive into our questions, would our guests like to briefly introduce yourselves to our listeners? Sandra, let’s start with you. 

Sandra: Hi everyone, I’m Sandra Igwe and I’m the founder and chief exec at the Motherhood Group. The Motherhood Group is a social enterprise that supports black mothers, birthing people in their pregnancy and beyond. 

Öznur: Great to have you on the podcast, Sandra. Rebecca? 

Rebecca: Hi everyone, I’m Rebecca, I’m a rare condition patient, and I also have the pleasure of chairing the recruitment working group of the Generation Study. 

Öznur: Fantastic, thank you, Rebecca. And over to you, Mathilde. 

Mathilde: Hi, I’m Mathilde. I’m leading design research on the Generation Study, and I have had the pleasure of working with Sandra and Rebecca and many others, trying to shape the processes and materials of recruitment and consent in the Generation Study. 

Öznur: Fantastic, thank you. Mathilde, let’s start with our first question. What is the Generation Study? 

Mathilde: Sure. So, whole genome sequencing is a technology that’s improving. We’re finding new ways of using that, and there’s interest globally to explore the use of this technology to screen for rare genetic conditions in babies, so that we can treat them earlier on, so they’re not having two different departments trying to figure out what’s wrong with them. And because we can look for hundreds of conditions with whole genome sequencing, it’s really much more efficient, and we’re able to look at these rare conditions, so it’s really exciting. There’s still a lot of questions about implementing this operationally within the NHS, and so the Generation Study is aiming to explore this. We’re going to be aiming to recruit 100,000 babies across England to take part in this, and they will be staying on the Generation Study for 16 years, or until they withdraw, so that we can see how their health develops, and really understand how genes affect their health. 

Öznur: Thanks Mathilde. And if you’d like to learn more about the Generation Study, you can listen to our previous Genomics 101 podcast called What is the Generation Study, and Which Conditions Will We Look for Initially in the Generation Study. 

Mathilde, can you briefly outline for us what we mean by design research? 

Mathilde: So, design research is a design and research methodology, which involves users from scoping through iteration. So, even back when we didn’t know this would be called the Generation Study and we weren’t even sure of the boundaries of that, we were involving parents, NHS staff and other users of the service to try and understand what it might be. And later down the line it went all the way through to iterations once we started having materials and a better idea of what it could be like (inaudible 0:04:18) with users outside of the company to understand what their needs are, what would work well for them, and how we can shape the whole service to do things better. 

Öznur: And how have we implemented design research in the Generation Study? 

Mathilde: Yep, so we’ve also done a lot of engagement, which was bringing public views in the form of public dialogues, so understanding which conditions should be looked for, what principles should be guiding that work, but also we’ve been involving users in regular rounds of codesign and usability testing to understand what works and what doesn’t work. It’s been around 105 people now that have taken part, and it’s only going to be growing. Involving users has been shown to improve the implementation of interventions in the healthcare context, so we really hope that this will help the Generation Study when it launches. And regular rounds of codesign have had to be balanced with ethics, operations, feasibility, but I’m proud to say that user perspectives have been central to the decisions of the programme throughout.  

Öznur: That’s fantastic to hear. I’m going to come to Rebecca and ask, why is it important for us to be guided by the patients and the participants? 

Rebecca: It’s absolutely central, and the public dialogue that really underpinned this, which started in 2020, the messages from that have really come through to the whole codesign process of the project. The public consultation really told us that people were genuinely keen about the project, but wanted to ensure that they were part of the process, and that coproduction really began from day one. This is a new world leading project. This has not been done before, so we needed a whole new approach to how we produced and how we designed this with patients and with parents, and that’s exactly what we’ve done. And why we have done it is because we know ultimately it leads to trust within the project, within the research study, which is essential, as I say, ‘cos this is a world first. But it also leads to better consent, a better pathway through the study, a better results pathway as well, and all the way through, ensuring that expectations are managed, that there is transparency, and people are fully informed and can make the right decision for themselves and for their baby.

Öznur: Thank you. And would you like to add something, Sandra? 

Sandra: Yeah, so I know from my community that we represent black mothers and black ethnic minority patients and participants, and we have very unique lived experiences that many research may not be privy to or just do not understand. And so engaging with patients from the community ensures that research is grounded in real authentic community needs and priorities. And also involving women like myself and those from my community, it can really help to identify and overcome barriers to inclusion or getting mums involved. I know I always hear, you know, “Sandra, black mothers are so hard to reach, they don’t really get involved in research.” Well, if you include those from the community to lead in the research or support in engagement, you will have a lot more uptake, and it leads to more accessible inclusive research, which of course everyone really, really desires to have more of.  

And then also participants from the community can flag issues and suggest solutions that researchers may miss, because it’s not knowledge, it’s experience. It’s, you know, having someone go through the experiences without necessarily studying it, but again lived experience to me, it’s more crucial than any other experience that you could possibly have. 

Öznur: 100 percent, lived experience is really, really crucial for us to make the services that we’re making really speak to the actual context of our users. Thank you for that. And Rebecca, how has this process been different to the 100,000 Genomes Project? What was your experience?

Rebecca: I was consented onto the 100,000 Genomes Project back in 2015, and I can remember that experience very vividly, on a cold, wet December afternoon, going off to meet my genetic counsellor, and receiving the consent form for the 100,000 Genomes Project, which was very much like War & Peace. Scratching my head at the time, going, “Gosh, I’m going to have to (inaudible 0:08:54) to go through this.” And then going home that evening and sitting on the sofa, and, you know, considering myself an educated woman, just realising I had so many questions. I really didn’t understand it, and I needed somebody to help me unpack this, and translate it. And I’m pleased to say that our consent process and our recruitment process is very different to this, which is a fantastic thing.

And what’s really key about the lessons that we have learnt from the 100,000 Genomes Project is that, to really build trust in a research programme and a new research programme, you need to manage expectations, and that’s wrapped up in building trust around the programme as well. And with the 100,000 Genomes Programme, there have been challenges and issues around that expectation management, and some expectations weren’t managed. And even now nearly ten years on, we are still feeling the effects of that, and patients and families are still feeling hurt because of that. So, we have learnt from that and therefore we have designed a process with patients and with parents. We know that no two experiences are the same, that we have to ensure that we remain flexible, and we have to ensure that we are addressing any misconceptions, any misunderstandings.

Perception and reality have to be treated the same. We have to understand how people are understanding genomics, because outside of pockets, genomics is not a standard NHS piece of healthcare. So, people come to this study with different assumptions, and we have to learn to go beyond them. We have to understand what their health literacy needs are, and how we can help manage that, how we can help translate, so that nobody is stuck at home on a cold, wet December evening, scratching their head, going, “Well, I don’t know what this actually means.” We are ensuring that the NHS professionals and everybody involved in the pathway is fully aware of how to explain the project, explain the risks, explain the benefits, and be fully transparent. And we know what the risks and the benefits are that need to be addressed because we’ve asked parents and patients as well.

So, we know the challenges and we’re trying to address them head on, and that’s essential. It’s essential in building trust, and that’s one of the key learnings from the 100,000 Genomes Project. And it has been brilliant to be involved in this project and really kind of learn from that past experience, but move forward in such a unique and fresh way that really will have benefit to those new parents.

Öznur: Thank you, Rebecca.

And we have been talking about the consent process in the context of newborns, and we know that, while consent given for newborn screening is really high in the UK, parents often leave this conversation relatively uninformed. Sandra, can you tell us a little bit about what you think the risks of not designing this consent moment appropriately might be?

Sandra: I guess not designing appropriately can break down trust. So, I think engaging in a variety of parents in this research and design is crucial for trust. And that’s a topic that’s come up many times in our community is that they believe that there is a lack of trust between research practitioners and this wider system as a whole, and the community of marginalised patients, parents, mothers. So, I think it’s really important that communities have this. But also researchers must make the effort to meet parents where they are at, not just physically but also conceptually, as well as emotionally. So, hosting conversations in familiar, comfortable community spaces is essential. We had our session in our hub, our community hub, and mothers were really familiar with the space and with each other as well. And so partnering with local grassroots organisations and leaders to create inroads is so beneficial, and I can hand on say that when you connect with the community, you’ve already done the first step in building trust.

And consent conversations should be guided by what matters most to each parent within each community, ‘cos every community’s different and every patient is different as well, and so that may require different focuses or different formats, or different messengers for different groups. And so we like to have people with lived experience from the community representing that, and also driving the uptake of consent as well. But failing to engage diverse voices can lead to perpetuating inequalities in access and uptake, so it’s really important to have representation because the lack of it in research can overlook communities’ specific concerns and needs.

Öznur: Absolutely, and that inclusion is really important for the study. Is there anything you’d like to add, Mathilde?

Mathilde: Yes. When we talk about consent, oftentimes we think about that one moment, the moment of conversation with a clinician, and signing on the dotted line, and I think what we have done here in the Generation Study is to consider recruitment from the very first time that they hear about the Generation Study all the way down to that moment. And it’s been really important because, yes, the moment of consent - you know, during pregnancy, you’ve got a lot of information coming in, a lot of different priorities, so you may be a little bit all over the place and not understand specific things, or not have the time to really spend thinking and understanding jargon, etc. And that presents a big risk because, when you may receive results, there may be confusion. There may be a loss of trust if there’s media coverage that talks about the Generation Study in a way different from what you had understood it. So, these are some of the risks that we’re trying to avoid. 

But the big risk is also, as Sandra has said, the risk of not engaging a wide variety of parents, not just in the moment of consent but the whole process. So, if we’re thinking about where we’re using the word genomic and how are we using that, this is a word that’s actually really scary for a lot of people. And we might be very proud of the cutting edge technology that we’re using, but actually it can sound very science-y and almost sci-fi to people. So to us, the moment of consent is really from the first time that you hear about the Generation Study, you start creating a mental model about what that means, all the way down to the consent moment, when the samples are taken, the results and beyond. It’s really been looking at this whole journey holistically.

Öznur: And that language point is a really interesting one. I know that the study is obviously being communicated to the public through posters, leaflets, websites, which speak to how the study works, you know, the conditions we test for, and the benefits and risks of joining. There’s a lot of language. There’s written words in there, there’s audiovisual content, videos, images. How did we inform what type of content is needed to communicate the depth of the study?

Mathilde: I think the example of the introduction video is a really good one, and I want to discuss this a bit with Sandra, because actually it was quite a crucial turning point. We tested the video several times in user research before and after the Motherhood Group workshop, but the thoughts that her community gave us really helped change the tone of this video from something very professional to a conversation between parents raising questions. I wonder, Sandra, if you remember what your community’s feedback had been, and if you can talk a little bit about that.

Sandra: Yes. So, the mothers from our community at the Motherhood Group definitely gave lots and lots of feedback that the initial posters didn’t really resonate with mothers from our community. They said that the visuals and the language felt a little bit generic and also too clinical, and it didn’t speak directly to our community. They also expressed that seeing more black parents and more black families represented signals for us too as well – so, seeing people like look like us in the posters and the media would have allowed a lot more uptake. So, narratives and videos featuring real people that looked like members of our community, they expressed that would go a lot further. And also it made them feel a lot more relevant, and again it goes back to the notion of having more trust and feeling less abstract, but more like an authentic way of engaging or directly communicating with our community.

They also appreciated the effort to be more upfront, but the risk and also the downside, not just selling only the positives. You know, members from our community were saying they wanted to know the real deal. And also our community have been misled in the past. You have to understand that. The history kind of shows that there has been a breakdown in trust, and so transparency, they shared, was really, really key to rebuilding that trust, as well as materials that are culturally tailored and designed for different formats for our community.

Mathilde: It’s really exciting how much this feedback has pushed all of us in the team and the designers – pushed us to think about how to talk about the Generation Study, what narratives to use, what tone of voice, but also you’ll see on the posters there’s space there to have photos of several different family types and people of different backgrounds. It’s not just one photo. And there’s also some very small tweaks, it seems like, but it actually has a very big impact, about what it is that you’re trying to say and what people understand in a split second when they’re seeing that.

Öznur: Absolutely, and that open dialogue is definitely key to keeping on bringing those perspectives in, and keeping updating and moving the language of the study as well. Obviously, the study will keep being shaped. I’m curious about how will design research continue to shape the Generation Study going forward.

Mathilde: Yep, so we will have an iterative process, where we’re still listening to the sides as they’re launching to hear what are the questions that are being raised, what are some of the challenges that they’re facing. At the same time, we have a survey that parents will be able to fill in, and we have an evaluation partner, UCL, who is doing an independent review of how well all of this is landing, and evaluating the work that we’ve been doing to see is it really hitting all of these points, and what we may need to be iterating or changing as we learn.

Rebecca: I should also point out that the recruitment working group is very much in the background, but we are still very much alive, and we will come back to look at those first pieces of feedback and to look at what the experiences have been, and how we can learn and how we can help kind of shape what comes next. Because it’s critically important that we have this always learning philosophy. It’s critically important that now, you know, the rocket has launched, how will it land, and we don’t know until we’ve actually had that feedback. So, we can plan and absolutely plan to the nth degree, but actually how it exists out there in the real world, we won’t know until the project goes live and that feedback comes through. And that’s what we’re also really excited about is to actually learn those first lessons and see how we can support going forward, and see what needs a tweak here, a change there. And again, it’s that dialogue that started with the public dialogue back in 2020, and here we are in 2024 and that dialogue will still continue, and we are still listening and we are still learning.

Öznur: Thanks Rebecca. I’d like us to reflect on the importance of continuous learning. What’s the importance of continuous learning in this project? I’ll start with Sandra.

Sandra: Continuous learning to me and my community really means listening to the voices that are often seldom heard. It means trusting and placing trust in the community to be a part of or lead or be involved in research, changes that affect our community. It also means actively and proactively working to rebuild that trust, because there’s been a lack of trust from the community, and that means transparency. It also means honesty, and it also means continuous involvement as well. There’s no point in involving us at the end of a study for our feedback, but at the very start to show that you are trying to be authentic. 

Rebecca: Ultimately, genomics is the science of people. Genomics is people, so we have to keep talking to the very people that we are looking to try and support, help, care for, and ultimately impact them and their families as well. So, I completely agree with Sandra, continuous learning, it’s a continuous dialogue, and understanding how our opinions differ, how our opinions may shape and grow as the general conversation about genomics continues as well in the public discourse. So, we have to understand and we have to stay sort of on our feet, that this is a dynamic conversation, therefore we need to change and we need to remain flexible as well. And if we keep our ears open and if we keep our minds open, then we will continue to build that trust, and we will continue to ensure that we have a robust study that will ultimately fulfil its research aims.

Öznur: Thank you. And Mathilde? 

Mathilde: I think there’s only so much that we could really cover in theory before we launched, and now, you know, it’s going to go out into the world, and there’s many things that we couldn’t have predicted that will happen. We have that humility to understand that. And what’s super important going forward is that we have a team there to keep kind of staying on our toes, listening to what’s happening, to make sure that we respond to that, so that, as Sandra said, it’s not enough to just ask people afterwards. It’s also not enough to engage just at the beginning and then stop listening once we’re live, once it gets hairy and a bit difficult. So, we are very excited to find out all the things that we hadn’t considered before we launched, and just continue to learn.

Oznur: We will wrap up there. Thank you to our guests, Rebecca Middleton, Sandra Igwe and Mathilde Leblonde for joining me today as we discussed the use of design research in the Generation Study. If you’d like to hear more episodes like this, please subscribe to Behind the Genes on your favourite podcast app. I’ve been your host, Öznur Özkurt. This podcast was edited by Bill Griffin at Ventoux Digital, and produced by Naimah Callachand.

In this explainer episode, we’ve asked Amanda Pichini, Clinical Director at Genomics England and Genetic Counsellor, to explain which healthcare professionals you may come into contact with in your genomic healthcare journey.

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 [email protected].

You can download the transcript or read it below.

Florence: Which healthcare professionals are involved in my genomic healthcare journey? I'm joined with Amanda Pichini, Clinical Director for Genomics England, and genetic counsellor to find out more. So firstly, when someone has a genetic or genomic test, what kind of healthcare professionals might they come into contact with? 

Amanda: Well, everyone has a different journey, and it can depend on the type of test you have and the reason for having it. Some tests might only look for a single gene. Some might look at many genes, and some look for a very specific gene change that's already known to be in someone's family. Some genomic tests are there to find the cause of a person's diagnosis, understand more about their cancer, or maybe to predict a future health problem that they may have or that's in their family. 

So usually people start with their GP, who they go to with a question about their health or their child's health, and this could lead to them being referred to a clinical genetic service or perhaps another specialist team.  

Florence: So, then what is the purpose of a clinical genetics team? 

Amanda: Well, a clinical genetics team, in brief, aims to provide people that have a genetic condition or are at risk of one with health information, including information about prevention, counselling support, and genomic testing, and they focus on the whole family. 

Adults and children can both be seen in a genetic service. Clinical genetics teams tend to focus on rare conditions and rare predispositions to certain types of cancers, so really anything that might have a strong genetic basis and could impact someone at any stage of their life. A clinical genetics team is made up of a range of roles, and that could include clinical genetics, doctors, genetic counsellors, clinical scientists, and administrative staff. 

Florence: Could you tell me a little bit more about each of those roles?  

Amanda: Sure. I am a genetic counsellor, so I'll start with that. Genetic counsellors are specially trained healthcare professionals that help patients and families understand information about their genomic health, as well as provide guidance and emotional support. 

So, this could be about understanding their family history, making informed choices about having a genetic or genomic test, or helping them to come to terms with a result or a new diagnosis and the impact that could have on them or their family. Clinical geneticists are medically trained doctors that specialise in genetic conditions. 

They understand the underlying ways that genetics can affect health, and they use that to help make diagnoses for patients. How about genomic scientists? These are often not seen directly by patients, but they're vital to someone's genomic healthcare journey. So clinical genomic scientists and genetic technologists work in labs, and they're involved in processing patient samples, working with those other healthcare professionals to select the most appropriate genomic tests to perform and interpreting those results based on the variance or genetic changes that are seen in patients, which are usually summarised in a lab report. 

There's lots of other healthcare professionals that can also, um, be in a clinical genetics team. That could include administrative staff, family history coordinators, genomic practitioners or genomic associates. They might help arrange appointments, gather medical and family history details after a referral to help the clinical team know what might be done next. 

Some genetic services also have psychologists, nurses, or other allied health professionals embedded in their team or in specialty clinics that they work with, and it's really important that everyone is working together as a multidisciplinary team to help those patients and families in their healthcare journey. 

Florence: So, we know there are lots of different healthcare professionals within the clinical genetics team. Are there any other professionals involved in genomic healthcare as well?  

Amanda: Absolutely. As genomics becomes part of routine healthcare, that means there's lots of other healthcare professionals involved in arranging genomic tests and giving back results, or at least having initial discussions about genomic tests before referring on to another specialist. 

So, some examples might be midwives, arranging screening tests for women in pregnancy, a number of those screening tests have a genetic or genomic basis. They might also refer families with a history of a genetic condition whilst they're pregnant for more specialist genetic testing. Many paediatricians are ordering genomic tests for children that might be suspected to have a syndrome or an underlying cause for their health or developmental issues. 

And many nurse specialists like those who work with people with cardiac conditions or neurological conditions. Might be involved in arranging or discussing genetic testing. Final example in the cancer world is oncologists who might often arrange genetic tests that will help give information about someone's cancer. 

The last thing to call out isn't necessarily healthcare professionals, but patient charity organisations are super crucial to someone's genetic healthcare journey. It's really important for families when they've had a new diagnosis or when they're seeking information, and there are some charities that do have healthcare professionals that work for them, like a nurse or genetic counsellor or psychologist that may help to run a helpline, for example. 

Florence: That was Amanda Pichini explaining which healthcare professionals are involved in a genomic healthcare journey. 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.