Dr Ana Lisa Tavares, Anne Lennox, Dr Meriel McEntagart, Dr Carlo Rinaldi: Can patient collaboration shape the future of therapies for rare conditions?

Rare condition research is evolving, and patient communities are driving the breakthrough. In this special Rare Disease Day episode, we explore the challenges and opportunities shaping the future of rare condition therapies. From groundbreaking gene therapy trials to the power of patient-driven research, our guests discuss how collaboration between families, clinicians, researchers, and regulators is paving the way for faster diagnoses, equitable access to treatments, and innovative approaches like nucleic acid therapies and CRISPR gene editing. With insights from Myotubular Trust, we follow the journey of family-led patient communities and their impact on advancing gene therapy for myotubular myopathy - showcasing how lived experience is shaping the future of medicine. However, while patient-driven initiatives have led to incredible progress, not every family has the time, resources, or networks to lead these research efforts. Our guests discuss initiatives like the UK Platform for Nucleic Acid Therapies (UPNAT), which aims to streamline the development of innovative treatments and ensure equitable access for everyone impacted by rare conditions. Our host Dr Ana Lisa Tavares, Clinical lead for rare disease at Genomics England, is joined by Meriel McEntagart, Clinical lead for rare disease technologies at Genomics England, Anne Lennox, Founder and CEO of Myotubular Trust and Dr Carlo Rinaldi, Professor of Molecular and Translational Neuroscience at University of Oxford. "My dream is in 5 to 10 years time, an individual with a rare disease is identified in the clinic, perhaps even before symptoms have manifested. And at that exact time, the day of the diagnosis becomes also a day of hope, in a way, where immediately the researcher that sent the genetics lab flags that specific variant or specific mutations. We know exactly which is the best genetic therapy to go after." You can download the transcript, or read it below. Ana Lisa: Welcome to Behind the Genes.    [Music plays]  Anne: What we’ve understood is that the knowledge and experience of families and patients is even more vital than we’ve all been going on about for a long time. Because the issue of there being a liver complication in myotubular myopathy has been hiding in plain sight all this time, because if you asked any family, they would tell you, “Yes, my son has had the odd liver result.”  There were some very serious liver complications but everybody thought that was a minor issue, but if we are able to engage the people who live with the disease and the people who observe the disease at a much more fundamental level we may be able to see more about what these rare genes are doing.  [Music plays]  Ana Lisa: My name is Ana Lisa Tavares, I’m Clinical Lead for Rare Disease research at Genomics England and your host for this episode of Behind the Genes. Today I’m joined by Anne Lennox, Founder and CEO of the Myotubular Trust, Dr Meriel McEntagart, an NHS consultant and Clinical Lead for Rare Disease Technologies at Genomics England, and Dr Carlo Rinaldi, Professor of Molecular and Translational Neuroscience at the University of Oxford.    Today we’ll be hearing about the importance of involving the patient community, particularly as new rare therapies are developed, and discussing the forward-facing work that’s happening that could have potential to unlock novel treatments for many rare conditions.  If you enjoy today’s episode we’d love your support. Please like, share and rate us on wherever you listen to your podcasts. Thank you so much for joining me today.  Please could you introduce yourselves.   Anne: I’m Anne Lennox, I’m one of the founders of the Myotubular Trust, a charity that raises research funds for and supports families affected by the rare genetic neuromuscular disorder myotubular myopathy.  Meriel: I’m Meriel McEntagart, I’m a consultant in clinical genetics in the NHS and I have a special interest in neurogenic and neuromuscular conditions.  Carlo: Hi, I’m Carlo Rinaldi, I’m Professor of Molecular and Translational Neuroscience at the University of Oxford. I’m a clinician scientist juggling my time between the clinic and the lab where we try to understand mechanisms of diseases to develop treatments for these conditions.  And I’m also here as a representative of the UK Platform for Nucleic Acid Therapies, UPNAT. Thanks for your invitation, I’m very pleased to be here.  Ana Lisa: Thank you. Meriel, I’d love you to tell us a bit about your work and how you met Anne, how did this story start?  Meriel: Thank you. Well prior to being a consultant in clinical genetics, I spent 2 years as a clinical research fellow in neuromuscular conditions, and as part of that training I worked on a project where the gene for myotubular myopathy had just been identified, and so there was a big international effort to try and come up with sort of a registry of all the genetic variants that had been found as well as all the clinical symptoms that the affected patients had, and then do kind of a correlation of the particular variant mutation with symptoms.   I worked when I was training to be a clinical geneticist because of my interest in neuromuscular conditions so when I eventually became a consultant at St George’s Hospital I was actually interviewed by the Professor of Paediatrics and he knew Anne and her son, when Anne was looking for more information about the condition he suggested that perhaps I might be a good person for Anne to talk to.  Ana Lisa: Thank you. Interesting connections. Anne, can you tell us your story and how this led you to found the Myotubular Trust?  Anne: Yes, thanks Ana-Lisa.  Well, as many families will tell you when they’re newly diagnosed with a rare disease, you go from knowing nothing about a condition to being one of the few deep experts in that condition because there are so few deep experts. So this happened to us in 2003 when our son, Tom, was born, and when he was born he was floppy and his Apgar scores, the scores they do on new-born babies, were pretty poor, and before long we knew that it was more than just momentary issues at birth.  And, cutting a very long story short, 5 weeks later he was diagnosed with this very rare neuromuscular genetic disorder that we didn’t know we had in the family.  We were told that this was a very serious diagnosis.    At that time – more than 20 years ago – over 80% of those boys didn’t make it to their first birthday and the stark statistic we had in our head a lot was that only 1% made it past the age of 10. And that has changed due to better ventilator and breathing equipment, etc, but at the time we expected that he might not make it to his first birthday.    We were very lucky, we had Tom longer than one year, we had him for nearly 4 years, 4 very lovely years where it was tough, but he was a really lovely member of our family.  Despite being really weak he managed to be incredibly cheeky and bossy, and he was a great little brother for his big sister. We were also very lucky that he was being looked after by Professor Francesco Muntoni, who is Head of the Paediatric Neuromuscular Service at Great Ormond Street. And, like Carlo, he is a clinical researcher and actually that I found to be amazing as a family member because you knew what was happening out there and Professor Muntoni, other than living with the reality day to day you want to know where things are going.    We began to realise that back then 20 years ago the more common rare neuromuscular diseases were finally beginning to get some fundamental research funds, like Duchenne, spinal muscular atrophy, and Professor Muntoni was very good at explaining to lay non-scientific parents like us that one day the technologies that would lead to a cure, that would re-engage proteins for other conditions and would translate down eventually into the possibility of replacing myotubularin, which is the protein not being produced or not being produced enough in myotubular myopathy. And then we began to understand actually what the barriers to that would be, that translating developments in more common, or let’s say more prevalent conditions, would be hard to do without some translation research being done; you could not just not lag years behind, you could lag decades behind if you haven’t done some other work.    So, I met Wendy Hughes, another mother, of a boy called Zak who was a few years older than Tom, and these were the days before social media, and it was amazing to be in contact with another family going through something similar and we had great conversations. But then they were also looked after by Professor Muntoni and we particularly began to develop the idea as 2 families that we might be able to raise some research funds towards this concept of keeping pace with the scientific developments.  And then we discovered there was no charity we could channel those funds through. Even the umbrella body for neuromuscular diseases who were covering 30 to 40 conditions, frankly, they just couldn’t trickle their funding down into investing in every neuromuscular disease, and slowly but surely it dawned on us that if we did want to make that difference we were going to have to set up our own charity.   So that’s what we eventually did and back in 2006, we founded what was actually the first charity in Europe dedicated to myotubular myopathy – luckily, more have come along since – and we were dedicated to raising research funding. In fact, it wasn’t our goal to set up another charity but around that time, about a year in, we happened to go to a meeting where the Head of the MRC, the Medical Research Council, was giving a talk and he said that in the last few years the MRC had begun to really realise that they couldn’t cure everything, that they couldn’t cure the diseases that would be cured in the next millennium from a top down perspective. There had to be a trick, there had to be a bottom up as well, because that was the only way this was going to happen. And I have to say that that was a really reassuring moment in time for us to realise that we weren’t just chasing pipe dreams and trying to do something impossible, that there was a role for us.    Ana Lisa: I think it would be really interesting for people to hear your story and the amazing set-up and fundraising that you’ve done, and at the same time it would be really good for us to reflect on how this isn’t feasible for every patient and every family and how we’re going to need to work cooperatively to move forwards with rare therapies.  Anne: When we explored the idea with Professor Muntoni and Meriel and others about setting up a charity one of the really reassuring things that Professor Muntoni got across to us was that this wasn’t about raising the millions and millions it would take to fund clinical trials but the issue in the rare disease space was funding the proof of principle work, the work where you take a scientist’s hypothesis and take it over the line, and the rarer the disease, the less places there are for a scientist to take those ideas. And the example he gave us was a piece of research like that might cost a hundred to a couple of hundred thousand, if you fund a piece of work like that and if it is successful, if the scientist’s principle gets proven, then behind you it’s much easier for the bigger muscle disease charities to also invest in it. It’s harder for them to spread their money across all the very rare diseases hypothesis out there, but if you’ve helped a scientist get over the line they’ll come in behind you and then they won’t be the ones who fund the tens of millions that it takes to run a clinical trial.    If it’s got potential, then that’s where the commercial world comes in, and that’s where the biotechs come in. So he’d given the example of if you spent £ten0,000 on a piece of research and it actually is proven, in behind you will come the bigger charities that would put in the million that takes it to the next phase, and in behind them will come the bio-checks that’ll provide biotechs that’ll provide the tens of millions.    And then, you know, a lot of what happens relies on serendipity as well, we know that, and you could easily run away with the idea that you made everything happen but you don’t, you stand on the shoulders of others. And our very first grant application in our first grant round, which received extraordinary peer review for how excellent the application was, was a £100,000 project for a 3-year project that had gene therapy at the core of it by a researcher called Dr Ana Buj Bello at Généthon in Paris. This piece of research was so promising that 18 months in she and another researcher were able to raise $780,000 and, as Professor Muntoni predicted, from the French muscle disease charity AFM and the American muscle diseases charity MDA.  And 18 months into that 3 years it was so promising that a biotech company was started up with $30 million funding, literally just on her work.    So that doesn’t always happen but, as Professor Muntoni explained, our job was not that $30 million, our job was that first £100,000, and our job was also to make ourselves known to the people in the neuromuscular field.  If you have lab time, if you have research time and you have a choice where you’re putting it there is a place you can go to for a myotubular myopathy related grant application, so it’s not just that this will come to us out of the blue, people will have done prior work, and our existence makes it worth their while, hopefully, to have done that prior work.  Ana Lisa: That’s an amazing story how you’ve set up this charity and how successful that first application for gene therapy was. I’d love to hear more about that gene therapy and did it get to the clinic and to hear that story from you.  Because I think there are a lot of learnings and it’s really important that the first patients who are treated, the first families that are involved, the researchers who start researching in this area, the first treatments lead the way and we learn for all the other treatments for all the other rare conditions that we hope and that together as a community we can share these learnings.  Anne: Yeah. I sometimes describe it a bit like going out into space. When you see a rocket going off look at how many people are behind and the amount of work that’s been done, the degree of detail that’s managed, and then you go out into space and there are a whole load of unknowns, and you can’t account for all of them.  Who knows what’s out there in this sphere.  But the amount of preparation, it feels similar to me now, looking back.  We were so idealistic at the beginning.  Our grant to Dr Buj Bello was 2008 and actually it is a really fast time in, the first child was dosed in the gene therapy trial in September 2017.  Ana Lisa: So, we’re talking less than 1 years.  Anne: Yeah. And in the meantime obviously as a charity we’re also funding other proof of principle research. One of the founding principles of the charity was to have a really excellent peer review process and scientific advisory board so that we wouldn’t get carried away with excitement about one lab, one research team, that everything would always come back to peer review and would be looked at coldly, objectively. I don’t know how many times I’ve sat in a scientific advisory board meeting with my fingers crossed hoping that a certain application would get through because it looked wonderful to me, and then the peer review comes back and there are things you just don’t know as a patient organisation. So, yes, in those 9 years we were also funding other work.  Ana Lisa: You’ve just given an interesting perspective on sharing the learnings between the scientists, clinicians, the experts in a particular condition, if you like, and the families, and I’d be really interested to hear your views on what’s been learnt about how families and the patient community can also teach the clinical and scientific community.  Anne: So, the first child was dosed in September 2017 and by the World Muscle Society Conference 2 years later in October 2019 the biotech had some fantastic results to show. Children who had been 24-hour ventilated were now ventilator-free, which, unless you know what it’s like to have somebody in front of you who’s ventilator-dependent, the idea that they could become ventilator-free is just extraordinary.    However, one of the things we’ve learnt about gene therapy is that we are going out into space so there are extraordinary things to be found, and extraordinary results are possible, as is evidenced here, but there is so much that we don’t know once we are dealing with gene therapy. So unfortunately, in May, June and August of 2020, 3 little boys died on the clinical trial. So we have a clinical trial where the most extraordinary results are possible, and the worst results are possible, and both of those things are down to the gene…  What we discovered and what is still being uncovered and discovered is that myotubular myopathy is not just a neuromuscular disorder, it is a disorder of the liver too, and these children didn’t die of an immune response, which is what everybody assumes is going to happen in these trials, they died of liver complications.    And one of the things that has come out of that, well, 2 sides to that. Number one is that it is extraordinary that we have found a treatment that makes every single muscle cell in the body pick up the protein that was missing and produce that protein, but also what we’ve understood is that the knowledge and experience of families and patients is even more vital than we’ve all been going on about for a long time. Because the issue of there being a liver complication in myotubular myopathy has been hiding in plain sight all this time, because if you asked any family they would tell you, “Yes, my son has had the odd liver result, yes.”    We could see something that looked like it was not that relevant because it was outside the big picture of the disease, which was about breathing and walking and muscles, but actually there was this thing going on at the same time where the children had liver complications. There were some very serious liver complications but everybody thought that was a minor issue but if we are able to engage the people who live with the disease and the people who observe the disease at a much more fundamental level we may be able to see more about what these rare genes are doing.  Ana Lisa: Yeah, thank you very much for sharing such a moving story and with such powerful lessons for the whole community about how we listen to the expertise that families have about their condition, and also I think the really important point about how we tackle the research funding so that we’re including and sharing learnings from the conditions that are initially studied in greater depth, and we hope that many more conditions will be better understood and more treatments found and that actually the learnings from these first gene therapy trials will really help inform future trials, not just for gene therapies but also for many other novel therapies that are being developed.  [Music plays] If you're enjoying what you've heard today, and you'd like to hear some more great tales from the genomics coalface, why don't you join us on The Road to Genome podcast. Where our host Helen Bethel, chats to the professionals, experts and patients involved in genomics today. In our new series, Helen talks to a fantastic array of guests, including the rapping consultant, clinical geneticist, Professor Julian Barwell, about Fragile X syndrome, cancer genomics and a holistic approach to his practice - a genuine mic-drop of an interview. The Road to Genome is available wherever you get your podcasts. [Music plays] Ana Lisa: Carlo, I would really like to come to you about some of the initiatives that are happening in the UK, and particularly it would be really interesting to hear about the UK Platform for Nucleic Acid Therapies as a sort of shining example of trying to do something at a national scale across potentially many different rare conditions.    Carlo: Thanks, Ana-Lisa. Thanks very much, Anne, for sharing your fantastic story. I mean, I just want to iterate that as clinician scientists we do constantly learn from experiences and constantly learn from you, from the patient community, and this is absolutely valuable to push the boundary. And I really liked your vision of a rocket being launched in space and I would imagine that this is a similar situation here. So, we are facing a major challenge. So, there is over 7,000 rare diseases in the world and with improvements of genetic diagnosis this is only increasing. So, in a way rare diseases is the ultimate frontier of personalised medicine and this poses incredible challenges.   So, you mentioned the bottom-up approach and the top-down approach and in a way, both are absolutely necessary. So your story is a fantastic story but also makes me think of all the other families where they don’t share perhaps the same spirit, you know, they are in areas of the world that are not as well connected or informed, where patient community simply cannot be ‘nucleated’, let’s say, around the family. So, there is definitely an issue of inclusivity and fair access.    So, what we’re trying to do at UPNAT, which is the UK Platform for Nucleic Acid Therapy, is to try to streamline the development both at preclinical and clinical level of nucleic acid therapies. So, we’ll start with antisense oligonucleotides just because those are the molecules of the class of drugs that are most ‘mature’, let’s say, in clinic. So, there are several antisense oligonucleotides already approved in the clinic, we know that they are reasonably safe, we understand them quite well, but of course the aspiration is to then progress into other forms of gene therapy, including gene editing approaches, for example.   And one of the activities that I’m involved, together with Professor Muntoni, is to try to streamline the regulatory process of such therapies and in particular curate a registry of, for example, side effects associated with nucleic acid therapy in the real world, and you would be surprised that this is something that is not yet available.  And the point is exactly that, it’s trying to understand and learn from previous mistakes perhaps or previous experiences more in general.    And this is very much in synergy with other activities in the UK in the rare disease domain.  I’m thinking of the Rare Disease Therapy Launchpad, I’m thinking of the Oxford Harrington Centre, I am thinking of the recently funded MRC CoRE in Therapeutic Genomics. These are all very synergistic. Our point is we want to try to amplify the voice of the patient, the voice of the clinicians working on rare disease, and we want to systematise. Because of course one of the risks of rare disease therapies is the fragmentation that we do all these things in isolation. And I would argue that the UK at the moment leveraging on the relatively flexible and independent regulatory agencies, such as the MHRA, on the enormous amount of genetics data available through Genomics England, and of course the centralised healthcare system, such as the NHS, is really probably the best place in the world to do research in the rare disease area, and probably I’m allowed to say it because I’m a non-UK native.       Ana Lisa: Thank you, that’s a brilliant perspective, Carlo, and across all the different therapeutic initiatives that you’re involved with. And, Carlo, presumably - we’re all hoping - these different initiatives will actually lead to ultimately a bigger scaling as more and more novel therapies that target both our RNA and DNA and actually are working, I guess further upstream in the pathway.    So classically in the past it’s been necessary to work out all the underlying biology, find a druggable target somewhere in that pathway and then get a larger enough clinical trial, which can be nearly impossible with many of the rare and ultra-rare conditions or even, as you’ve said, the sub-setting down of more common condition into rarer subtypes that perhaps can be treated in different ways.  And with the many new different treatments on the horizon, ASO therapies, as you’ve said, is a place that’s rapidly expanding, and also crisper gene editing. I’d be really interested to hear your reflections on how this might scale and also how it might extend to other new treatments.  Carlo: Yeah, that’s exactly the right word, ‘scaling up’. I mean, there will be of course very unique challenges to every single rare disease but I would argue that with genetic therapies, such as ASOs or crisper gene editing, the amount of functional work that you need to do in a lab to prove yourself and the scientific community that this is the right approach to go for can be certainly very important but can be less just because you’re addressing very directly because of the disease.    And then there are commonalities to all these approaches and possibly, you know, a platform approach type of regulatory approval might serve in that regard. You know, if you are using the same chemistry of these antisense oligonucleotides and, you know, similar doses, in a way the amount of work that you need to produce to again make sure that the approach is indeed a safe approach and an effective approach might be also reduced.    I would say that there are also challenges on other aspects of course, as you were saying, Ana-Lisa. Certainly the typical or standard randomised placebo control trial that is the standard and ultimate trial that we use in a clinical setting to prove that a molecule is better than a placebo is many times in the context of rare diseases simply not possible, so we need to think of other ways to prove that a drug is safe and is effective.   This is something that we all collectively as a scientific community are trying to address, and the alliance with the regulatory agencies, such as the MHRA, and you said that you have found your interaction with the MHRA very positive, and I can tell you exactly the same. So we are all trying to go for the same goal, effectively, so trying to find a way to systematise, platformise these sort of approaches. And I guess starting with antisense oligonucleotides is really the right place to go because it’s a class of drugs that we have known for a long time, and we know it can work.  Ana Lisa: Meriel, can you tell us a little about the National Genomic Research Library at Genomics England and how this could link with initiatives to find many more patients as new treatments become available for rare and ultra-rare conditions?  Meriel: Yes, I think what’s wonderful now is actually that what we’re really trying to do is give everybody the opportunity to have their rare condition specifically diagnosed at the molecular level, and the way in which that is being done is by offering whole genome sequencing in the NHS currently in England but to all patients with rare diseases.    And so, it’s about trying to establish their diagnosis. And as well as that, even if the diagnosis isn’t definitely made at the first pass when the clinical scientists look at the data, because the whole genome has been sequenced, actually all that information about their genome, if they consent, can then be put into the National Genomics Research Library.  And that is a fantastic resource for national and international researchers who get approved to work in this trusted research environment to make new disease gene discoveries and identify these diagnoses for patients.  What’s also offered by Genomics England as well is when the National Genomics Library data results in a new publication, the discovery of a new gene or perhaps a new molecular mechanism that causes a disease we already know about, that feeds back into the diagnostic discovery pathway within Genomics England back onto the diagnostic side of all the data.    So, patients who may have had genetic testing previously using whole genome sequencing where they’ve, if you like, had their sequencing done before the diagnosis was sort of known about, will also be picked up. And so, what this is really doing is trying to kind of give this really equal platform for everybody having testing to all have the same opportunity to have their diagnosis made, either on the diagnostic side or with research.  Ana Lisa: So, sort of on a cohort-wide scale as new discoveries are made and published you can go back and find those patients that may actually have that diagnosis and get it back to them, which is brilliant.  Meriel: Exactly. And this speeds up the whole process of getting these diagnoses back to people. So on a regular basis in the NHS, we will get feedback from the Diagnostic Discovery Pathway about “Here’s some patients who you requested whole genome sequencing from a number of years ago and actually now we think we know what the particular molecular condition is.”  And so, it’s key of course for our patients with rare conditions to make that molecular diagnosis because then we’re able to have them identified for our colleagues who are doing this ground-breaking research trying to bring therapies for these rare conditions.  Ana Lisa: Thank you. And I hope that, as currently, if a novel genetic mechanism, as you’ve just described, is identified that could explain a rare condition that those patients can be found and they can receive that diagnosis, even many years later, and hopefully as novel treatments become available and say there’s a chance to individualise ASO therapies, for example, to start with, that one could also go and look for patients with particular variants that could be amenable potentially to that treatment. And that’s really sort of exciting that one could look for those patients across England, irrespective of which clinic they’re under, which specialist they’re under, and I think that could be really powerful as new treatments develop. I suppose, Meriel, if somebody comes to see you now in clinic are things different?  Meriel: Well, I think one of the things for me when patients come to clinic now is we might have an idea about what we think their condition is, maybe even we think it’s a specific gene. And we can offer whole genome sequencing and so it’s not just the way we used to do things before by looking just at the coding regions of the gene, we can find more unusual ways in which the gene can be perturbed using whole genome sequencing.  But let’s say we don’t make the diagnosis. I encourage my patients, if they’re comfortable with it, to join the National Genomics Research Library, because really it’s been incredibly productive seeing the new genetic discoveries that are coming out of that, but as well I say to them, even if we don’t get the diagnosis the first time round when we look at the data, actually this is a constant cycle of relooking at their data, either if they’re in the NGRL or as well on the Diagnostic Discovery Pathway side of the service that’s run by Genomics England. So yeah, I feel like it’s a very big difference; they don’t have to keep coming every year and saying, “Is there a new test?” because actually they’ve had an excellent test, it’s just developing our skills to really analyse it well.  Ana Lisa: Yes, and our knowledge, the technology and the skills keep evolving, certainly.  And I think one of the things that I’m sort of hearing from this conversation is that balance of hope and realism, Carlo we were talking about earlier how you need all the pieces of the puzzle to be lined up - so the regulatory agency, the clinicians, all the preclinical work has to have been done, monitoring afterwards for side effects - every piece of the puzzle has to be lined up for a new treatment to make it to a patient.    And, Anne, I’d like to come back to you because we’ve talked about this before, how one balances these messages of optimism and hope which are needed for bringing everybody together as a community to crack some of these very difficult challenges highlighted by treatments for rare and ultra-rare conditions and at the same time the need for realism, a balance conversation.  Anne: Yeah, that was one of our big learnings through the gene therapy trial and other trials we’ve had in the condition. As a rare disease charity, you do everything. You know, my title is CEO, but I tell people that’s Chief Everything Officer because there’s only a few of you and you do everything. So, you go and you lead the London Hope Walk and you also are a layperson on the Scientific Advisory Board and you also send out the emails about grants... And so, you could easily as a small rare disease charity conflate different communication messages because you’re in a certain mode.  And so we have been from the early days in the mode of raising hope for people to say, “Look, we can make a difference as a patient community, we could raise funds, we might be able to move things forward, you’ve got the power to make a difference if you want to.” That’s one set of hope.  And it’s not dreamlike hope, we’re linked to the reality of there are great breakthroughs.  So, you know, in the world of spinal muscular atrophy these clinical trials have led somewhere very quickly, so we’re not selling false hope, we’re talking about the difference we can make.    But then as soon as you flip into “There’s a clinical trial being run” that’s a completely different type of communication and you cannot conflate that message with the previous message.  And we always say to everybody, “We’re your team, we’re a family, we’re a team, we all help each other.  When you are considering joining a clinical trial your team is the clinical trial team.    The other team does other things for you but the people you need to work with and ask hard questions of and listen hard to, that’s your clinical trial team led by the principal investigator because then you’re in that with them. And, you know, the reality of the fact that many, many clinical trials don’t work as we wish they would be and the decision you make for your child, your baby, your little one, to join a clinical trial… because that’s what it comes down to in our disease, has to be made with that team, not the team that’s selling you a fundraising event. It’s worth reminding rare disease patient organisations we’re wearing different hats and the hope and the realism are different tracks you have to go down.    But at the same time as being realistic you also have to keep remembering that there is still grounds for hope, we are moving forward. And 21 years ago, when Tom was born the idea that you would be able to get all of the muscles in the body to switch back on – putting it in lay terms – seemed like a bit dream. Well, that is what has happened in the gene therapy clinical trial, we just have to now make it safer and understand more about what we’re dealing with. So, the 2 things, the hope and the realism, do exist side by side.  Ana Lisa: I think that perfectly encapsulates a lot of the messages around rare disease therapies where there’s such hope that novel treatments will really target directly the DNA or RNA to potentially correct the problem across many different rare conditions and therefore actually making treatments one day suddenly available to a much, much bigger population of people with rare conditions than we could’ve dreamt of 20 years ago or perhaps now, and at the same time this massive need to work cooperatively to all make this as fair, as equitable. Not everybody is going to have the opportunity to fundraise massively to be an expert about their condition, and the importance of sharing these learnings and also really, really listening to the patient community and really, as Carlo was saying, keeping track of side effects, having registries/databases to share these is going to be incredibly important.  [Music plays]  Ana Lisa:  Anne, can you tell us a little about your reflections on equity from the patient community perspective?  Anne: Well I mentioned serendipity early and one of the aspects of serendipity that played into our favour for setting up the Myotubular Trust was that by hook or by crook Wendy Hughes, who set up the charity with me, and I were both able to devote time at that period of our lives to setting up a charity. When my husband, Andrew, and I were told that Tom would more than likely die before his first birthday, one of the decisions we made as a family was that he would never not be with a parent, we would always have someone around, and that kind of meant someone had to give up a full-time job and that was me.  We thought, “If Tom has a few scarce months on the planet, we’ll be with him.” And then when Tom lived to be nearly 4, as a family we got used to living on one salary and we were very lucky that we could pay the mortgage that way and run our family that way and eventually that meant I had the time to run the charity.    That doesn’t happen that easily, that’s a tall order, particularly when you have somebody in the family who has such high needs. And one of the things that I have often thought about is that in the rare disease space we could do with a different funding model for rare disease charities, we could, in an ideal world I have this nirvana that I imagine where there’s a fund that you can apply to that is contributed to by the people who make profits out of finding rare disease cures - so the pharmaceutical companies and the biotechs - and there’s a fund that they contribute to and that if you have a rare disease and you are willing to set up an organisation that supports families, that raises research funds, that provides a way of hearing the patient voice, then you could apply to that for running cost funds and then you’d be able to run this charity. And then you wouldn’t have to rely on whether you live in an area where people will raise money for you or…  We were very lucky that we came across a few great benefactors who would give us money for running the charity, which is actually how we fund it.    All the research money we raise goes 100% into research, not a penny of it goes towards running costs because we have serendipitously found people who will be benefactors for the charity, but we’re relying on a lot of good luck for that kind of model to work. And when you look at how much profit is made from developing rare disease treatments and cures – which is fine because that’s what puts the passion and that gets people working on it – then why not have an advance fund to run rare disease charities? One of my nirvana dreams.  Ana Lisa: It’s good to dream. Indeed, my hope is that there will be some amazing shining examples that lead the way that open doors, make things possible, prove that something can work and how and that then that will enable many other treatments for many additional rare conditions to be added in so that if you’ve learnt how this particular treatment modality works for this rare condition and there was funding behind it and everything else that’s needed that then you can, the learning from that, I’m going to use the word ‘tweak’, which sounds minor and could be very major but actually the concept that you can then tweak all those learnings and findings so that that same type of treatment modality could be adapted to treat somebody else with a different rare condition in a different location would be absolutely incredible and really powerful, given that if something like 85% of rare conditions affect less than one in a million people it’s not going to be feasible to use the same strategies that have been used in the past for very common conditions.    One of the other big barriers is the cost of developing treatment for ultra-rare conditions.  Where it’s a small number of patients that you have and therefore all the challenges that come with monitoring, checking for efficacy, monitoring safety and ultimately funding the challenges are much greater, however if some of these treatment modalities are also going to be used to treat common conditions it might be that actually there’s a lot more cross-talk between the nano-rare, ultra-rare, rare and common conditions and that we can share a lot of that learning. I’d love to hear from each of you where you hope we will be for rare disease and rare therapies.  Carlo: Well my dream is that in 5 to 10 years’ time an individual with a rare disease is identified in the clinic, perhaps even before symptoms have manifested, and at that exact time the day of the diagnosis becomes also a day of hope in a way where immediately the researcher, the centre, genetics lab, flags that there are the specific mutations, we know exactly which is the best genetic therapy to go after, antisense oligonucleotides as opposed to CRISPR editing, and a path forward, both at the preclinical and clinical level, to demonstrate and to cure these patients eventually is already laid out in front of the patient.  So, transforming the day of their diagnosis as a day of hope, this is my dream with the next ten years.  Ana Lisa: Thank you, that’s a wonderful dream. Meriel, can I come to you?  Meriel: Yes, I think I just want to echo Carlo.  We’ve had great developments and progress with getting whole genome sequencing into the NHS for testing but what we really need is for it to be fast and efficient and getting those diagnoses established quickly. And we have had that set up now and we’re really getting there in terms of speed, but then what we need is exactly what’s the next step and actually structure like UPNAT that are developing these processes that we can then say to the patient, “And from there, now that we’ve established your diagnosis, this is what we have options to offer.”  Ana Lisa: Brilliant. And presumably that if the diagnosis isn’t achieved now there is a hope that it will be achieved in the future as well. Anne...  Anne: Well, stepping one hundred per cent into the patient’s shoes rather than the scientific side that we don’t so much influence....  stepping in the patient’s shoes, in 5 years’ time I would absolutely love it if we were in a situation where all the parties that have come to the table looking at a therapy or in the earlier research genuinely want to bring the patient voice into the room. As Carlo talked about, there’s even going to be more and more and more of these rare diseases, then those voices, those few people who have experience of it, they may be able to shed light on something. Maybe even sometimes don’t even know it’s a fact that they know but that were brought to the table as passionately as everything else is brought to the table.  [Music plays]  Ana Lisa: We’ll wrap up there. Thank you so much to our guests, Anne Lennox, Carlo Rinaldi and Meriel McEntagart, for joining me today as we discuss the collaborative power of working together and look to the future of rare therapies that could have the potential to unlock treatments for many rare conditions. 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, Ana-Lisa Tavares. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.  

In this episode, our guests explore the impact of genetic discoveries on inherited retinal dystrophies, in particular retinitis pigmentosa (RP). The discussion highlights a recent study that identified two non-coding genetic variants linked to RP, predominantly in individuals of South Asian and African ancestry. The conversation highlights how advances in whole genome sequencing are uncovering previously hidden causes of genetic disease, improving diagnostic rates, and shaping the future of patient care. It also addresses the challenges faced by individuals from diverse backgrounds in accessing genetic testing, including cultural barriers, awareness gaps, and historical underrepresentation in genomic research. Our host Naimah Callachand is joined by researcher Dr Gavin Arno, Associate Director for Research at Greenwood Genetic Centre in South Carolina, Kate Arkell, Research Development Manager at Retina UK, and Bhavini Makwana, a patient representative diagnosed with retinitis pigmentosa and Founder and Chair of BAME Vision. We also hear from Martin Hills, an individual diagnosed with autosomal dominant retinitis pigmentosa. To access resources mentioned in this episode: Access the Unlock Genetics resource on the Retina UK website Visit the BAME vision website for more information and support Find out more about the groundbreaking discovery of the RNU4-2 genetic variant in the non-coding region which has been linked to neurodevelopmental conditions in our podcast episode   "Discoveries like this lead to better clinical management. We understand better the progression of the disease when we can study this in many individuals from a wide spectrum of ages and different backgrounds. We can provide counselling as Bhavini was talking about. We can provide patients with a better idea of what the future may hold for their eye disease, and potentially, you know, we are all aiming towards being able to develop therapies for particular genes and particular diseases."   You can download the transcript or read it below. Naimah: Welcome to Behind the Genes.   Bhavini: The few common themes that always come out is that people don’t really understand what genetic testing and counselling is. They hear the word counselling, and they think it is the therapy that you receive counselling for your mental health or wellbeing. There is already a taboo around the terminology. Then it is lack of understanding and awareness or where to get that information from, and also sometimes in different cultures, if you have been diagnosed with sight loss, you know blindness is one of the worst sensory things that people can be diagnosed with. So, they try and hide it. They try and keep that individual at home because they think they are going to have an outcast in the community, in the wider family, and it would be frowned upon).  Naimah: My name is Naimah Callachand and I am Head of Product Engagement and Growth at Genomics England.  I am also one of the hosts of Behind the Genes. On today’s episode I am joined by Gavin Arno, Associate Director for Research at Greenwood Genetic Centre in South Carolina, Kate Arkell, Research Development Manager at Retina UK, and Bhavini Makwana, patient representative.  Today we will be discussing findings from a recently published study in the American Society of Human Genetics Journal which identified two non-coding variants as a cause of retinal dystrophy in people commonly of South Asian and African ancestry. If you enjoy today’s episode, we’d love your support. Please like, share, and rate us on wherever you listen to your podcasts.  Okay, so first of all I would like to ask each of the three of you to introduce yourselves. Bhavini, maybe we’ll start with you.  Bhavini: Hi, I’m Bhavini Makwana, patient representative, and also Chair of BAME Vision. I have other roles where I volunteer for Retina UK, and I work for Thomas Pocklington Trust.  Naimah: Thanks Bhavini. Gavin.  Gavin: Hi, my name is Gavin Arno, I am Associate Director for Research at the Greenwood Genetic Centre in South Carolina, and I am Honorary Associate Professor at the UCL Institute of Ophthalmology in London.  Naimah: Thanks Gavin. And Kate.   Kate: Hi, I’m Kate Arkell, Research Development Manager at Retina UK.   Naimah: Lovely to have you all today. So, let’s get into the conversation then. So Gavin, let’s come to you first. First of all, what is retinitis pigmentosa and what does it mean to have an inherited retinal dystrophy?  Gavin: So, retinitis pigmentosa is a disorder that affects the retina at the back of the eye. It is a disease that starts in the rod photoreceptor cells. So, these cells are dysfunctional and then degenerate causing loss of peripheral and night vision initially, and that progresses to include central vision and often patients will go completely blind with this disease. So, retinal dystrophies are diseases that affect the retina. There are over 300 genes known to cause retail dystrophy so far, and these affect different cells at the back of the eye, like retinitis pigmentosa that affects the rods. There are cone rod dystrophies, ones that start in the cone photoreceptors, macular dystrophies that start in the central retina, and other types of retinal dystrophies as well.  Naimah: Thanks Gavin. And Bhavini, just to come next to you. So, you received a diagnosis of retinitis pigmentosa at the age of 17 after a genetic change was found in the RP26 CERKL gene. At this time only ten other families in the UK had been identified with this type of genetic alteration. Would you mind sharing a bit more about your journey to your diagnosis?  Bhavini: Yeah. So, at the age of 17 is when I got officially diagnosed with retinitis pigmentosa, but leading up to that I was experiencing symptoms such as night blindness. So, I struggled really badly to see in the dark, or just in dim lighting, like this time of the year in winter when it gets dark quite easily, all my friends from college could easily walk across the pavement, but I struggled. I was bumping into a lot of things. Like things that I wouldn’t really see now that I know my peripheral vision, I was losing that, so like lamp posts or trees or bollards, I would completely miss or bump into them. I was missing steps, and had a really, really bad gaze to the sun. Like, everything was really hazy. That continued and I just put it down to stress of exams. You know, just given that age and where I was at the time of my life. But then it kind of continued. So, I went to the see the optician who then referred me, and after months of testing I got diagnosed with retinitis pigmentosa. Back in the late 90s when I was diagnosed there wasn’t really anything about genetic testing, or cures., or treatments. I was basically just told to get on with it, and that was it.   It was only until about 15/16 years later I came across Retina UK, started understanding what retinitis pigmentosa is, and what it means, and then when I was offered genetic testing and counselling at one of my annual Moorfields appointments, they explained to me what it involved, what it could mean, what kind of answers I would get, and I agreed to take part. It was a simple blood test that myself and both my parents took part in.      Naimah: Thanks for sharing that Bhavini. So, I know you were able to receive a diagnosis through whole genome sequencing in the 100,000 Genomes Project after the alteration in the gene was found, and this was found in the coding region of the genome. But in this study that we are talking about in this podcast, we know that the two genetic changes that were found, they were in the non-coding region of the genome. Gavin, could you tell me in simple terms what the difference is between the coding and non-coding region of the genomes and why these findings are significant in this case?   Gavin: Yes, sure. So, the human genome is made up of about 3 billion letters or nucleotides which are the instructions for life essentially. Now, within that human genome there are the instructions for roughly 20,000-25,000 proteins. This is what we call the coding genome. These are the bits of DNA that directly give the instructions to make a protein. Now, we know that that part of the genome is only roughly 2% of the entire genome, and the remaining 98% is called the non-coding genome. Now, we understand that far less well. We have a far poorer understanding of what the function of the non-coding genome is versus the coding genome. So, typically molecular diagnostic testing or genetic testing is focused on the coding genome, and historically that has been the fact. Now with advances in genome technologies like whole genome sequencing and the 100,000 Genomes Project, we are able to start to look at the non-coding genome and tease out the previously poorly understood causes of genetic diseases that may lie within those regions of the genes.   Naimah: Thanks Gavin, I think you have just really highlighted the possibilities available with looking at the non-coding region of the genome.  Kate, coming to you next. I wanted to talk about the importance of uncovering and understanding genetic causes of inherited retinal dystrophies, and how do discoveries like these change the landscape of care for patients with inherited retinal dystrophies?  Kate: So, getting a genetic diagnosis can really help families affected by inherited retinal dystrophy. It helps them and their ophthalmologists to better understand their condition, and in some cases gain some insight into possible prognosis, which helps people feel a lot more in control. It can also potentially inform family planning decisions and even open up options around access to reproductive technologies for example, not only for the individual, but sometimes also for their close relatives. Of course, researchers are making great strides towards therapies, some of which have reached clinical trials. But a lot of these approaches are gene specific, so for people who know their genetic diagnosis, they are more able to recognise research that is most relevant to them and quickly pick out potential opportunities to take part. At the moment it is still the case that around 30% of our community who have a genetic test will not receive a clear result, and that can feel very frustrating. So, the more discoveries like this that are made, the better.   Naimah: Thanks Kate.  So, now we are going to hear a clip from Martin Hills, our Retina UK patient representative who has been diagnosed with autosomal dominant retinitis pigmentosa. Martin has undergone genetic testing and shares more about his experience.  Martin: My name is Martin Hills, and I was officially diagnosed with autosomal dominant retinitis pigmentosa in 2001, and because of that I immediately had to stop driving which made a huge impact both on myself and my family.  My eyesight has slowly deteriorated over the years. It first started with difficulty seeing at night, and also playing some types of sport, which I think probably was in my 20s. My peripheral vision has been lost slowly and now has completely gone. Fortunately, I still have some reasonable central vision left which is a great help. I am registered as severely sight impaired, and I am also a symbol cane user. My father and aunt were both diagnosed with this condition, and my daughter has been relatively recently, as has altogether eight members of our wider family, and that also includes two younger generations. In 2015 I went for genetic counselling and testing and at that time it was for 176 genes known to be associated with retinal dystrophies. I believe that has now gone up to about 300, but at the time they couldn’t recognise what my faulty gene was, and that has still been the case to my knowledge to date.   I have also been part of the 100,000 Genome Project along with several others of my wider family, and I am also a participant in the UK Inherited Retinal Dystrophy Consortium RP Genome Project, which has been sponsored by Retina UK. The impact of not having a positive genetic test result is quite interesting and has really been a rollercoaster. I guess it is all about hope, and to start with when I knew I was going to be genetically tested, I think my first reaction was optimism, and I think if you have a positive test result, that is a real hope for the future. I think that is quite exciting particularly as things seem to be progressing so rapidly. But because I didn’t get a positive result, the next reaction I had really was disappointment because I felt one step behind people with a positive result. Of course the natural reactions are one of frustration, and then I guess followed by realisation of the situation, and heading towards trying to adjust and making coping strategies for the future.  I still feel that genetic testing for all forms of medical conditions is so important and has a huge future in understanding and then potential treatments for so many medical issues. I guess it might be a bit too late for me, but if I can contribute to finding a restorative treatment for the younger generations of my family, and for that matter other people, then I think that is good enough for me.   Naimah: So, we have just heard from Martin that although he has not been able to have a positive genetic test result, his involvement in various studies may have benefits in helping others find treatment. So, I guess on that point Bhavini, maybe you could comment, or ask you how you felt whenever you were about to get a diagnosis through whole genome sequencing?  Bhavini: Yes. When I got called in almost three and a half years after the testing that took place was a massive, massive relief because not only did I get genetic counselling before the testing period, but I got called in and I spoke to a genetic counsellor who explained what they had been able to find and what kind of RP it was, how it would progress, and just answer so many questions. I am the mother of two daughters and even having two children, I lost a lot of sight after my first daughter, but at that time there wasn’t any evidence or there wasn’t any … you know, there was nothing I even knew about what questions to ask or anything, so I did go on to have a second child and drastically lost more sight. I had always been told, because the lack of awareness and understanding of RP in my family, and I am one of four children, and I am the only one that has it, so there is no other family history. Now I know it could have skipped generations, but I was always told things like it was karma. I must have done something in my past life. I was told to kind of have these herbs or these remedies to cure my sight loss, you know my RP. I was even desperate enough to kind of …  all these bogues treatments that you find online. You know, anything. I was so desperate to find anything that would help me.   When I received that testing and the counselling, it explained so much about how my daughters may or may not be affected, how they are carriers, and that was explained to me, how it would progress. So many questions and worries that I had for almost a decade and a half, they were answered. And not only for me, for my family, and all those people that told me all these sorts of things that I used to worry about that could have caused my RP. I was able to explain it to them and they understood that it was nothing to do with me being bad in my past life. It was actually you know, there is something scientific about it. So, it kind of gave me lots and lots of answers, and actually I then created a private Facebook page just with my RP26 CERKL genetic that I have been diagnosed with, just to see if there is anybody else out there, because when I was diagnosed, I think at the time I was told there was only myself and nine other families in the UK diagnosed with this particular gene. Now, I haven’t been that active on it, but you know there are people across the world who found my post and joined the group, and we share experiences about the age that we were kind of diagnosed, the kind of rate the symptoms have developed. It is so fascinating because we have got such similar experiences.   There is parents on there who are there on behalf of their children, and it is just so nice to see … I know it is RP, but the specific gene and the rate of which we have experienced all the symptoms, it is quite similar. So, it has been quite supportive and helpful and reassuring to my family including my daughters.  Naimah: That’s incredible Bhavini and it’s really nice that you have created that group and created kind of like a support network for all the other families that have been affected by the same genetic condition as well. Yeah, that’s incredible. Gavin, I know the findings in the study show that the genetic changes in this study are more common in people of African and South Asian ancestry. So, so I want to understand why is this an impactful finding in the study?  Gavin: Yes, so Kate mentioned that around 30% of people with inherited retinal dystrophies who have genetic testing don’t get a molecular diagnosis and we are working in my research lab and many other research labs to improve that. Now, that figure is very much higher in patients of for example African ancestry in the UK, and this is partly due to the fact that historically and even now genetic studies have been focused on European individuals and taken place in the US, and the UK, and Europe, and wealthy countries across the world. This means that people of African ancestry are poorly represented in genetic studies, not just genetic studies of genetic disease, but population studies as well. So, we have less of an understanding of the genetic variants found in the genomes of individuals of African ancestry. So, that means we solve less of the genetic cases, particularly at Moorfields we published a paper on this several years ago with the diagnostic rates in European patients versus those of African ancestry, and it was very, very much lower. So, we need to do better for those patients, and this study identified a cause of retinitis pigmentosa in 18 families of African ancestry who were recruited to the 100,000 Genomes Project.   This is a fairly large proportion of the patients with RP of African ancestry seen at Moorfields Eye Hospital, and when we contacted collaborators around the world many more families were identified, and I think we ended up publishing around about 40 families who were affected by this particular mutation. So, we can look at that variant, we can look at the DNA sequence around that variant, and we found there is a chunk of DNA around the mutation in the gene that was coinherited by all of those different individuals. So, this is what we call an ancestral haplotype. It’s an ancient variant that goes back many, many generations and it has a fairly high carrier frequency in genomes of African ancestry. So, we think this will be a fairly significant cause of retinitis pigmentosa across the continent of Africa. And so, identifying it will enable us to provide a molecular diagnosis for those families. Potentially there will be many more families out there who don’t know they have this cause of disease yet. They may be affected but they haven’t yet received genetic testing.   But discoveries like this lead to better clinical management. We understand better the progression of the disease when we can study this in many individuals from a wide spectrum of ages and different backgrounds. We can provide counselling as Bhavini was talking about. We can provide patients with a better idea of what the future may hold for their eye disease, and potentially you know we are all aiming towards being able to develop therapies for particular genes and particular diseases. As Kate mentioned many of the gene therapies are gene specific, so if we identify a cause of disease that is predominant like this and affects many, many people, then of course there is more interest from the pharmaceutical industry to develop a therapy for that specific gene.  Naimah: Thanks Gavin. I think that really does showcase how impactful these findings really are. Kate, can I come to you. So, Gavin touched on it there that people with African and Asian ancestry are significantly less likely to get diagnosed, but why is it important to ensure that these groups are represented in the genomic datasets?  Kate: So, we need to ensure that genetic testing and diagnostic accuracy works for everyone, and not just those of European ancestry. So, as Gavin said if the datasets don’t reflect the genetic variations seen in African or Asian populations, then the tests based on those data are more likely to give incomplete results for those groups of people. We really need a diverse range of genetic information for researchers to work on. As it is clear from this study’s results, populations from African backgrounds for example may have unique genetic mutations linked to retinal dystrophy. So, if those are really underrepresented in datasets based on European populations, that is obviously going to present a problem. Gavin mentioned access to treatment. We need to overcome some of these disparities in healthcare access, and   inclusion of broad spectrum of genetic data is actually a foundation for that.   Naimah: Thanks Kate.  So underrepresented groups are often less likely to know about genetic testing due to a combination of social economic and systemic factors that create barriers to access information. Cultural taboos can also play a significant role in shaping attitudes towards genetic testing, and I think Bhavini you kind of touched on this slightly with some of your experiences. I wonder, did you experience any of these cultural taboos?  Bhavini: Yes, some of them, but I think by the time I was informed about what genetic testing and counselling is I had come across Retina UK and I had already started having that background knowledge, so when that was offered to me, I actually had a basic understanding. But as Chair of BAME Vision I work with a lot of ethnic communities, and when I speak about my own personal experience about receiving genetic testing and counselling, I kind of break it down into my own language, and the few common themes that always come out is people don’t really understand what genetic testing and counselling is. They hear the word counselling, and they think it is the therapy that you receive counselling for your mental health or wellbeing.  So, again there is already a taboo around the terminology. Then it is lack of understanding and awareness, or where to get that information from. Also sometimes in different cultures, if you have been diagnosed with sight loss, you know blindness is one of the worst sensory things that people can be diagnosed with, so they try and hide it. They try and keep that individual at home, because they think they are going to have an outcaste in the community and the wider family, and you will be frowned upon, people will talk really bad.   So, it is not really common knowledge, so they don’t even talk about it. So, there is a lot of layers to unpick there. That is one of the priority areas in 2025 that we at BAME Vision are going to be working on to try and raise that awareness in different communities about what genetic testing is, what it could mean, how to get genetic testing if it is not offered to you at your own clinic. There is a lot of work I know Retina UK have done, so working with them, and how we can reach different communities to raise that awareness.  Naimah: That’s great. You have touched on how important the education piece is. I wonder, do you have any other examples of how healthcare providers and genetic counsellors might better engage communities to ensure that they are receiving the care that they need?  Bhavini: Yeah, absolutely. So, I think having information in different languages is essential, and I don’t expect to have lots and lots of leaflets in different languages. Whether it is audio form or whether there is different professionals within that setting that speak different languages that can communicate to those patients, or even their family or friends that could translate. I think language is definitely something. And having representation, so like different people who have accessed this and sharing their story and going out into community groups and sort of sharing those messages, is definitely what has been working for us, and we have been doing that on other topics that we have used.  Naimah: Yes, they all sound like really important ways to try and engage with different communities. You have already mentioned how amazing that Retina UK have been and the support that you have received from them. So, I wonder Kate, if you could tell us a bit more about the support that is available for those with inherited sight loss, and how these resources can support people from underrepresented groups as well.  Kate: So, we have a range of support services at Retina UK most of which involve our fantastic team of volunteers, one of whom is Bhavini, who are all personally affected by inherited retinal dystrophy themselves. So, they are all experts by experience so to speak. The team also does include members of the Asian community as well. So, if somebody makes a call to our helpline, they will be able to speak to somebody who genuinely understands what they are going through, which can be a lifeline for those who are feeling isolated and especially I think as Bhavini mentioned, if they feel unable to talk openly with their own family and certainly within their community. We have a talk and support service that offers ongoing more regular telephone support as well as in-person and online peer support groups where people can make social connections with others in similar situations. I think Bhavini has mentioned that she herself runs our London and Southeast local group.  We also have an information resource called Unlock Genetics. That explains genetics in understandable language and clearly explains how people can access testing and what that will involve. So, we have stories on there from people who have gone through the process and talk about that. So, that is available on our website, and we can provide it in audio format as well.  Naimah: So Gavin, looking to the future, what does this research mean for patients with sight loss and their families? What does this mean in the future?  Gavin: So, I think now that we have access to whole genome sequencing through projects like the 100,000 Genomes Project, we are able to start the process of understanding new causes of disease that are found outside of the coded region.  So, we can now look for non-coding variants that cause disease which was previously not possible because genetic testing was focused on 2% of the genome. As we make discoveries like this these will inform future studies. So, the more we identify this type of variant and are able to functionally test the effect on the gene or the protein, we are able to use that information to lead future tests. What this needs is large population datasets to be able to analyse these sorts of variants at scale. The more genomes we have the better our understanding will be of our population frequencies, and the key thing is here for inherited retinal dystrophies, all of these variants that we are identifying are very, very rare. So, we only find them in a very small number of individuals affected with disease, and an infinitely smaller number of individuals in the unaffected general population. So, the larger that population dataset is that we can study, the better we can understand the rarity of these variants and pick those out from the many, many millions of non-pathogenic or harmless variants that we find in the genomes of all the individuals.  Naimah: Do you think the paper will help lead the way for diagnosis of other conditions in African and South Asian communities?    Gavin: Yes. The better we understand causes like this, and we are now at the point where most of the genes that cause retinal dystrophy have been identified already, so the remaining causes to be identified will be these more difficult to find cases, non-coding variants, structural variants, which we haven’t touched on today which are larger rearrangements of the genome. These things are harder to find, harder to interpret, so the more that we find like this, the better our ability will be to interpret those sorts of variants. There are many similar findings coming out of genome studies like 100,000 Genomes Project. For example, there was a significant finding recently published on a non-coding RNU gene which causes a significant proportion of neurological disorders in the 100,000 Genomes Project. You need these studies to be able to drive forward the research in areas like this.   Naimah: Thanks Gavin, and the discovery that you are mentioning is the RNU4-2 gene that was discovered earlier this year. You can hear more about that on our other podcast on our website which is ‘How has groundbreaking genome work discovery impacted thousands far and wide’ to learn more about that as well. But yeah, I agree it is another really great example of how impactful these findings can be. Okay, we’ll wrap up there. Thank you to our guests Gavin Arno, Kate Arkell, and Bhavini Makwana for joining me today as we discussed the findings from a recent study which has identified genetic changes responsible for retinal dystrophy, and people commonly of South Asian and African ancestry. 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 have been your host and producer, Naimah Callachand, and this podcast was edited by Bill Griffin of Ventoux Digital.

In this episode, our guests discuss the potential of large-scale health datasets to transform research and improve patient outcomes and healthcare systems. Our guests also delve into the ethical, logistical, and technical challenges that come with these programmes. We hear how organisations such as UK Biobank, Our Future Health, and All of Us are collecting rich, diverse datasets, collaborating and actively working to ensure that these resources are accessible to researchers worldwide. Hosting this episode is Dr Natalie Banner, Director of Ethics at Genomics England. She is joined by Dr Raghib Ali, Chief Medical Officer and Chief Investigator at Our Future Health, Professor Naomi Allen, Professor of Epidemiology at the Nuffield Department of Population Health, University of Oxford, and Chief Scientist for UK Biobank, and Dr Andrea Ramírez, Chief Data Officer at the All of Us Research Program in the United States. "There are areas where academia and the NHS are very strong, and areas where industry is very strong, and by working together as we saw very good examples during the pandemic with the vaccine and diagnostic tests etc, that collaboration between the NHS and academia industry leads to much more rapid and wider benefits for our patients and hopefully in the future for the population as a whole in terms of early detection and prevention of disease." You can download the transcript or read it below.  Natalie: Welcome to Behind the Genes   Naomi: So, we talked to each other quite regularly. We have tried to learn from each other about the efficiencies of what to do and what not to do in how to run these large-scale studies efficiently. When you are trying to recruit and engage hundreds of thousands of participants, you need to do things very cost effectively. How to send out web-based questionnaires to individuals, how to collect biological samples, how the make the data easily accessible to researchers so they know exactly what data they are using.   All of that we are learning from each other. You know, it is a work in progress all the time. In particular you know, how can we standardise our data so that researchers who are using all of us can then try and replicate their findings in a different population in the UK by using UK Biobank or Our Future Health.    Natalie: My name is Natalie Banner, and I am Director of Ethics at Genomics England. On today’s episode we will be discussing how we can unlock the potential of large health datasets. By that I mean bringing together data on a massive scale, including for example genomic, clinical, biometric, imaging, and other health information from hundreds and thousands of participants, and making it available in a secure way for a wide range of research purposes over a long time period.   Through collaboration and industry partnerships, these programmes have the potential to transform research and deliver real world benefits for patients and health systems. But they also come with challenges ranging from issues in equity and ethics through to logistics, funding, and considerable technical complexities. If you enjoy today’s episode, we would love your support. Please like, share, and rate us on wherever you listen to your podcasts.     I’m delighted to be joined today by 3 fantastic experts to explore this topic. Dr Raghib Ali, Chief Medical Officer and Chief Investigator at Our Future Health. Professor Naomi Allen, Professor of Epidemiology at the Nuffield Department of Population Health, University of Oxford, and Chief Scientist for UK Biobank, and Dr Andrea Ramírez, Chief Data Officer at the All of Us Research Program in the United States.   Andrea, if I could start with you. It would be really great to hear about All of Us, an incredibly ambitious programme in the US, and maybe some of the successes it has achieved so far.   Andrea: Absolutely. Wonderful to be here with you and thank for you for the invitation. The All of Us Research Program started in 2016 from the Precision Medicine Initiative and was funded with the goal of recruiting 1 million or more participants into a health database. That includes information not only from things like biospecimens including their whole genome sequence, but also surveys that participants provide, and importantly linking electronic health record information and other public data that is available, to create a large database that researchers that access and use to study precision health.   We have recruited over 830,000 participants to date and are currently sharing available data on over 600,000. So, we’re excited to be with your audience, and I hope we can learn more and contribute to educating people listening about precision medicine.   Natalie: Thank you, Andrea. And not that this is competitive at all, but Raghib, as we are recording this, I understand the Our Future Health programme is marking quite a phenomenal milestone of 1 million participants. Would you mind telling us a little bit about the programme and something that you see as the benefits of working at scale for health research.   Raghib: Thank you very much. So, Our Future Health is a relatively new project. It was launched in 2020 with the aim of understanding better ways to detect disease as early as possible, predict disease, and intervene early to prevent common chronic diseases. Similar to All of Us, we are creating a very large database of participants who contribute their questionnaire data, physical data, genetic data, and linkage to healthcare records, with the aim as I said, to really improve our understanding of how best to prevent common chronic diseases.   So, we launched recruitment in October 2022. Our aim is to recruit 5 million participants altogether, and in the last 2 years about 1.85 million people have now consented to join the project. But you are right, as of last week we have what we call 1 million full participants, so people that have donated a blood sample, completed the questionnaire, and consented to link to their healthcare records. In our trusted research environment, we now have data on over 1million people available for researchers to use.   Of course, we have learnt a lot from the approach of UK Biobank, which we are going to hear about shortly, but the resource is open to researchers across the world, from academia, from the NHS, from industry, so that will hopefully maximise the benefits of that data to researchers, but as I say with a particular focus on early detection, early intervention, and prevention research.   Natalie: Thank you Raghib. Great to have you with us. Naomi, Raghib mentioned that UK Biobank has been running for a long time, since 2006.  It is a real success story in terms of driving a huge range of valuable research efforts.  Could you talk to us a little bit about the study and its history and what you have learned so far about the sort of benefits and some of the challenges of being able to bring lots of different datatypes together for research purposes?   Naomi: Yeah, sure. So, UK Biobank started recruiting 0.5 million participants in 2006 to 2010 from all across the UK with a view to generating a very deep dataset. So, we have collected information on their lifestyle, a whole range of physical measures. We collected biological samples, so we have data on their genomics and other biomarkers. Crucially because they recruited 15+ years ago, we have been able to follow up their health over time to find out what happens to their health by linkage to electronic healthcare records. So, we already have 8,000 women with breast cancer in the resource, cardiovascular disease, diabetes, and so on.   But perhaps most importantly, not only does it have great data depth, and data breadth, and the longitudinal aspect, is the data is easily accessible to researchers both from academia and industry, and we already have 18,000 researchers actively using the data as we speak, and over 12,000 publications already generating scientific discoveries from the resource.      Natalie: So, we have got 3 quite different approaches. Recruiting in different ways, different scale, different depth of data collection and analysis, but all very much around this ethos of bringing lots of different datatypes together for research purposes. I wonder if you could talk a little bit about how you might be sort of working together, even though you have got slightly different approaches. Are there things that you are learning from one another, from these different data infrastructures, or how might you be looking in the future to work together to address some of the challenges that might come up from working at scale?      Naomi: So, we talk to each other quite regularly. We have tried to learn from each other about the efficiencies of what to do and what not to do in how to run these large-scale studies efficiently. When you are trying to recruit and engage hundreds of thousands of participants, you need to do things very cost effectively. How to send out web-based questionnaires to individuals, how to collect biological samples, how to make the data easily accessible to researchers so they know exactly what data they are using.   All of that we are learning from each other, and you know it is a work in progress all the time. In particular, how can we standardise our data so that researchers who say are using All of Us can then try and replicate their findings in a different population in the UK by using UK Biobank or Our Future Health. So, can we come up with common standards so that researchers can better directly compare the data that they are using? So, we are in close contact with each other.   Natalie: Fantastic, thank you. And Andrea, from your perspective obviously you are collecting data in the US. Are you finding ways of working internationally and with other infrastructures like Biobank and Our Future Health around things like data standards? It sounds like something simple, but I can imagine it is quite complex in practice.   Andrea: Absolutely, and that dialogue and understanding and learning from each other both informally in meetings and talking as well through the published literature. So, all of these datasets are actively widely used, and seeing what is coming out in publications helps us know what researchers are doing with the data. And when you see different researchers either generating hypotheses from our datasets in a different way, or testing hypotheses differently, that helps us understand where some benefit might be added to our dataset or where we really may need to grow in a different direction to meet some other research needs.   I think that every study design always struggles with that balance between knowing exactly what we want to study and therefore building very specific questions and very specific protocols, but also allowing for the knowledge that we don’t really know all of the discovery we need to make and bringing in datapoints that will really generate those new hypotheses for the future.     I think for our study in particular, UK Biobank has been so remarkable in this way, helping structure All of Us to be able to contact our participants like UK Biobank and say, “Hey, we didn’t really know what we were going to get, but we have put all this wonderful data together and now we need to do a deeper dive.”   So, the engagement and long-term return of those UK Biobank participants has really enriched our data, and we have learnt from UK Biobank a lot there, and hope through growing our partnerships programme that we can continue to create partnered research opportunities to strengthen that data as well. That is a new thing coming out of our group. You may have heard of it previously as ancillary studies, but we recognise the partnership that is important for those research opportunities. So, we are reporting here that we are hoping to rebrand it to reach a larger audience, and that is led by Dr. Shelley, as partnered research opportunities that will allow us to re-contact, bring our participants back, and really deepen that dataset.   Natalie: Thank you. And Raghib, I know that it is a really important part of the Our Future Health model about going back to participants, but you are in quite early stages of working out what those opportunities might look like.   Raghib: Yes, very much early stages. Just to reiterate the point for me personally, having started my research in the UK about 20 years ago, I have certainly learnt a lot personally, but we have all learnt a lot from the model that UK Biobank established in terms of collecting data and providing it to researchers, and I see these 3 studies as very much complimentary.   All of Us again have done a lot more work in terms of providing feedback to participants about their risk of disease and genetic information, and as you say Our Future Health was set up deliberately to not just be a purely observational study, but to give participants feedback about their risk of different chronic diseases as well as the opportunity to take part in not just studies to collect data, but also interventional studies to see if we can change the natural history of disease and prevent diseases in our participants.   So, that has never really been done at scale before, and that is certainly a big challenge for us to do, not just in the UK, but anywhere, including the US and working with health systems as to how best to do that. So, you know we have spent the last 2 years really trying to understand how best to recruit participants and to provide data to researchers for the next couple of years, and long beyond that we will be looking really as to how we can maximise the benefits of providing feedback to participants and taking part in interventional studies.   Naomi: I think one way in which we can all learn from each other actually, is we know how to recruit hundreds of thousands of people, the general population, into research study, and the next challenge is how do you keep engaging them, telling them what you are doing. You can't collect everything when they first join the study, or they would be with you for days. So, what UK Biobank has been doing is sending out web-based questionnaires, a couple a year, to find out extra information about health outcomes, lifestyle factors. Inviting them back to specific assessment centres.   So, we are inviting 100,000 participants back for imaging, and then again over the next few years for a second scan. So, I think the real challenge here is once you have recruited them, how to find that right cadence of engaging those participants to keep contributing their data and their biological samples to really maximise the value of the dataset for research. That is an ongoing challenge for all of us. But I have to say, the UK Biobank participants, they are an amazing group of individuals, very altruistic.   Our Future Health and All of Us, we don’t give feedback, so there is nothing in it for our participants other than knowing that their data may help the future health of their children, and their grandchildren, and the rest of the world. So, that is very humbling, to know that the data that they have generated, and we have collected on them, is being used in that way.   Natalie: That’s a really interesting point, Naomi, about the difference between a research study that is designed for answering a particular question. You gather specific data for a specific purpose, and when it comes to recruiting participants into that you can be very clear about what it is you are trying to do.   But of course, for all of these programmes, the whole nature of them is that you are collecting a lot of data over a long period of time, and it could be used for all sorts of different purposes. You can't say at the outset exactly what those purposes might be and what those outcomes might be. So, there is a really interesting question, and of course I would say this with my ethics hat on, a really interesting question around sort of participant trust and confidence in those programmes.   Naomi, you spoke just then about one way of retaining engagement and retaining people’s interest, but I wonder Raghib and Andrea, if you have got thoughts on those sort of questions of how you can create that environment where participants can trust what you are doing with data over a long period of time, when you can't at the point at which they consent, say exactly how that data might be used? You have got a sense of the kinds of purposes, but you can't be too specific         Andrea: Sure. We know, and I have learnt from my own peers in this role, that enrolment in the study isn’t the end point of engagement. All of Us’s approach on engagement has been communicating with the entire community and really being there in the community, and that has been very powerful.   One effort over the last year we are proud of has been what we are dubbing participant driven enquiry, and that is where we say, “Thank you participants. We have gotten a ton of data out there for use, and funded researchers to use it all the time, but what do you, the participants, really want?” We were able to then take papers that researchers write and help tell participants and explain it in lay language, so the participants can say, “Hey, I have a question. Could you answer that for me?” Maybe we can, maybe we can't, but it has been very interesting to hear what participants want to know, and that participant driven enquiry project has turned out to be a big opportunity there.    The question they came to was not easy. Certainly, we didn’t expect an easy question, but they came to us asking, “Why is my diabetes worse than someone else’s? Is it the environment? Is it my genome? Is it my access to care? Why can't my diabetes be as well controlled as someone else’s?”  So, that has been huge, to interact directly with our participants and help really close the loop by answering questions in the language of research and show them how their data is contributing back.    Natalie: Thank you. And Raghib, how are you sort of grappling with these questions, particularly because you are recruiting so very heavily at the moment?   Raghib: So, as you say it is a challenge, and people do join the programme primarily based on trust that we will use their data for public health benefit and for the benefit of the whole population, but they also join on the basis that they will get back information about their own health and their risk of disease. To do both of those is not straightforward. I mean, the first of those, it has been well established by UK Biobank, and about 80% of our participants also say they are doing it primarily for to altruistic reasons, which is great. But 80% also said they would like to receive feedback about their own health, which is also understandable, and so we need to find ways to provide that in a timely way, but also in a way that the health service can manage. That is going to be one of our key challenges going forward.    But to echo what Naomi and Andrea have said, I mean to maintain participant’s engagement with the programme is not easy. We need to make sure that they are receiving information regularly, are kept up to date with what we are doing with their data, with the work that we are doing with academia, with the NHS, with industry etc. It is easier now than it was before because Our Future Health has been set up as a digital cohort, so we have means of communicating much more easily with our participants. But yeah, as you say we are at early stages. Over time that does get harder, to maintain that engagement. So, we know in the next one to 2 years we need to step up our work on feedback and recontact.   Natalie: Fantastic. I really love the idea of like the participant-led enquiry. That is something that I think our participant panel at Genomics England would really like to hear more about.   So, speaking about sort of ongoing engagement with participants, one of the challenges we know around recruiting into large-scale studies like this is that many research datasets don’t have equal representation from all communities. That might have an impact on the quality, the representativeness of the scientific outputs that you can generate, and potentially the benefits back to patients and participants.   How are you addressing this challenge in recruitment where you may have some communities that are not as engaged with scientific research. You may have elements of distrust or people being marginalised, having difficulty accessing research and these sorts of opportunities. Do you have any examples of what has worked really well? Raghib, if I could come to you first.   Raghib: Sure. So, I mentioned I worked on UK Biobank about 20 years ago. One of the things I was looking at then was how we could maximise participation, particularly of people from ethnic minorities into the project. Because of the age group that was chosen by UK Biobank for very good reasons, age 40 to 69, the proportion of people from ethnic minorities was relatively small. So, although it was representative for that age group, I think it was about 6%, or 34,000 out of the 500,000, that were from non-white ethnic minorities.   So, when Our Future Health was set up, we knew that the population has changed anyway. You know, the UK has become a much more ethnically diverse society. But also, because it is a cohort from 18+ and I think minorities tend to be younger on average than the white population, we knew we had an opportunity to really have a big step change in the number of people that could take part in a study like this. So, our aim is actually to get 10% of the whole cohort from ethnic minorities, so 500,000 out of the 5 million from ethnic minorities. Actually, so far we are pretty much on track. So, of the 1.8 million that have consented, about 180,000 are from non-white ethnic minorities.   That is extremely important, particularly for genetic research where non-European populations are very much underrepresented in nearly all genetic databases. Secondly, from a UK context, although it applies of course in all countries, is that people from more deprived backgrounds are also less likely to take part in this type of research. So again, we have made a very deliberate attempt to try and ensure we have adequate numbers from the most deprived quintile. Again, about 10% of the cohort so far, nearly 200,000 are from that most deprived quintile who both are underrepresented in research, but also have the worst outcomes. So, this is really our first study that has been big enough in the UK to look at that group properly and understand some of the factors at an individual level that we haven’t been able to in the past.   Finally, geographically, so the first time again because it is a digital cohort, we were able to recruit people from all over the UK. So, every single part of the UK is now represented in Our Future Health, particularly coastal communities and rural areas that haven’t been able to take part in this type of study before, as well as Northern Ireland. You know, for the first time we have got that full geographical coverage.   Natalie: Fantastic. I suppose a lot of that recruitment approach has very much been about going to where people are, rather than expecting them to come to you. Is that right?     Raghib: That is right and thank you for reminding me. So yeah, we have had a different approach. So, we have opened up many, many more clinics than previous studies through a combination of mobile units, shopping centres, community pharmacy. Community pharmacy in particular has been very important. So, to date we have had about 400 different venues that we have been able to recruit. That is over 1 million people that have given blood samples, and that has really enabled people from every part of the country to take part. Secondly, we have kept clinics open in areas of greater deprivation and ethnic diversity much longer than in other areas, to maximise the opportunity for them to join. Thirdly, we do provide reimbursement for people with expenses to ensure they aren’t excluded because of financial reasons, and again that has helped.    Natalie: So, really making those efforts is evidently paying off. Andrea, have you had similar experiences as All of Us? What has your approach been to try and ensure that you are getting a wider representation from different communities?    Andrea: It has really been a focus on the programme from the start to engage those who have not been included in research in the past and make sure the opportunity is there to participate. Our Engagement Division, led by Dr. Corrine Watson has really pioneered reaching those communities here in the US.   I think one other thing I will mention that we think about when we think about how to engage participants and reach people to return value back to those communities, is to make sure the people who are accessing the data also represent them, and we can build diversity within that researcher workforce. So, since our data was first released in 2020, we have recognised that the biomedical workforce also has a huge group of underrepresented individuals, and a lot of our researcher engagement and researcher outreach has focused on reaching those of diverse backgrounds and career paths.   To that end we have reached out and engaged historically black colleges as well as other minority serving institutions, really looking to make sure that their students and researchers can have the same access as more traditional research-based institutions in the US system.    That has been important because our system is built on cloud-based architecture and shared data that doesn’t require a huge cluster on campus, and that helps remove a barrier that some of those institutions and researchers may have had. We also know they haven’t been able to participate in the past, and we think that cloud architecture again can make the data much more feasible and be a huge support to diversifying the researcher workforce as we go forward. That circling back, helping them be the voices speaking to their community, helps build out that diverse participant community base as well.    Natalie: That’s such an important point, because it is not just about the participants and the data you can collect, but also who is able to look at it? Who is actually able to undertake the research?    Naomi, can I bring you in here? I know that UK Biobank has been thinking a lot about researcher access to data and trying to ensure that the data that you hold, the really rich datasets you hold in UK Biobank, are more accessible to researchers from different backgrounds who may not have the same level of resources. Can you tell us a little bit about the work you have been doing on that?   Naomi: Yeah. So, just following on from what Andrea said, it is really important to get as diverse ideas as possible from across the global research community to really move public health forward.   So, what UK Biobank has done is we are putting mechanisms in place so that early career students, and career researchers, and researchers at all levels of their career from lower income countries, can access the data at a much lower fee. So, currently for most researchers it costs about £9,000 to access all of the data. So, that is 40 petabytes of genomic data, biomarkers, clinical outcomes, lifestyle factors and so on. So, early career researchers and those in lower income countries, it is about £500.   On top of that a group of big pharmaceutical companies have got together to create a global researcher access fund, which essentially covers this reduced fee so that all researchers no matter where they are from have exactly the same opportunity to access the data to advanced scientific discoveries. So, on top of that all our researchers now use our online secure research analysis platform. While there is no charge to access the platform, there are costs associated with compute needed to analyse and store the results.    So, AWS have donated research credits for early career researchers and those from lower income countries up to a total of about $500,000 per year, to use the research platform. So, researchers can apply to use these research credits to offset the costs of compute and storage. So, that means that we are trying to democratise access to researchers from all around the world.   I think actually our biggest challenge is not so much … we have largely dealt with you know subsidising the cost. It is actually making researchers from lower income countries aware that these resources exist, and that are applicable to them.   So, sometimes we hear from say researchers in Africa or South America, “Well, there is no point accessing UK Biobank because it is not relevant to our population.” You know, a third of our researchers are from China. So, even if UK Biobank hasn’t got coverage of those racial ethnic populations, that doesn’t mean that the associations that you find between risk factors and disease risk are not applicable to other different populations. And that is also why having different resources like UK Biobank, like Our Future Health, like All of Us, in different populations around the world, is so important in order to replicate those findings.    Natalie: Absolutely, and fantastic just to hear the attention that is being paid to trying to ensure that diversity of different types of researchers who will just bring different questions to the table, different perspectives on the data, different priorities, different types of questions.    So, speaking about that diversity of researchers, one really important part of his ecosystem that we haven’t really touched on so far is around the role of industry. There are a lot of really important research questions being addressed by industry. Some that can only really come from, maybe it is pharmaceuticals, maybe it is tech.   From your perspectives, what kind of role can and should industry and commercial partners play in supporting the kinds of long-term research studies that you have set up, and ultimately trying to get to that point of sort of generating benefits back to patients and health systems. Naomi, can I start with you, for that sort of longer-term perspective for Biobank?   Naomi: So, industry are great partners for long-term studies like ours because they can bring additional funding, expertise, and technology. So, for UK Biobank, because it is so easily accessible to industry and academics alike on exactly the same terms, what it has meant is that industry, particularly big pharma and also now big tech, they can access the data, they see the value of the data for their own research purposes, and then they have invested into UK Biobank to do whole-exome sequencing, whole genome sequencing, proteomics at scale to increase the value of the dataset for their own drug discovery pipelines.   But of course, it means that the data that they have generated, which cost millions of dollars to generate, when you need deep pockets to do these kinds of study enhancements, then become available to all researchers. So, having access to these large-scale resources that have deep data on genomics, physical measures, other biomarkers, and clinical outcomes enables pharma to rapidly increase their drug discovery pipelines in generating new drugs and treatments for patients, and also those data are then shared with the rest of the global research community.     So, we found it to be a really exciting win/win in which industry get what they need to help move forward new drug targets and discovery, but also other researchers get what they need in order to make other scientific discoveries in different fields of research.        Natalie: Thank you. And Raghib, I know that for Our Future Health, that industry relationship is a really important part of the founding model. Will you tell us a little bit about how you are engaging and working with industry partners?   Raghib: Sure. So, as you said Our Future Health was set up in a different way, as a very public private partnership. Although the largest funder is the UK Government, more than half of our funding has come from a combination of life science companies, so pharmaceutical, diagnostic companies, as well as the medical charities, so the larger medical charities in the UK. That partnership is deliberate for all the reasons that Naomi has outlined. There are areas where academia and the NHS are very strong, and areas where industry is very strong, and by working together as we saw very good examples during the pandemic with the vaccine and diagnostic tests etc, that collaboration between the NHS and academia industry leads to much more rapid and wider benefits for our patients and hopefully in the future for the population as a whole in terms of early detection and prevention of disease. So, we have 16 life sciences companies that have joined as founding partners with Our Future Health who have contributed financially to the programme.    Equally importantly they have also contributed scientifically, so there is a huge amount of scientific expertise in industry, and they work with us with our Scientific Advisory Board with our scientists internally to think about the best use of the resource for drug discovery, diagnostics, new medical technologies, and new targets etc.    So, that is the vision, and so far, it is working well. It is a relatively new model to have set up a project like this in this way, but it has been a very collaborative approach, and we all recognise, all have similar aims, so recognise what we are working towards. You know, we meet regularly. We have a Joint Founders Board where as I say academia, NHS, industry, and the charities come together to decide on the priorities for the coming years.   Natalie: Fantastic. And Andrea, I suppose in the US it might be slightly different culturally from the UK, but the role of industry with All of Us, how are you engaging with those pharmaceutical, technology bodies, and partners as well?     Andrea: Absolutely, and maybe this goes back a bit to your first question. We at All of Us love learning from UK Biobank and have really seen them forge a lot of wonderful partnerships that have enriched and developed their dataset. We at All of Us have started with academia and working through partnership opportunities really intramurally at intramural centres that make up parts of the National Institute of Health. We believe that building on those close friends and family relationships we have both in the government and academia get us through our first step to be able to interface with commercial organisations. That really started with taking the first step this year to ensure broad availability of data that can maximise both use of the data available, as well as look forward to our partnership opportunities in the future.   So, commercial organisations as of 2024 have also been able to access the All of Us dataset that is that first step in thinking about what a partnership would be, and we are glad to build on the access that international organisations and academic organisations already have.   Natalie: A lot to look forward to here. We are going to have to wrap up in a moment, so I’d just like to leave you all with a final question before we have to end the podcast. There is huge ambition in all of the research programmes that you are leading and involved in, but what are you most excited about coming down the line in the next few years? What do you think is going to be feasible? What really gets you excited about the work that you are doing and where you see the potential benefits really landing in the next few years? Andrea, would you like to start?   Andrea: Thanks. There is a lot we are really excited about. I haven’t had a chance yet to mention our paediatric cohort, and that in addition to expanding access for international research, in 2024 we were able to enrol our first paediatric participants. That really sets up the potential to observe participants across the lifespan. That is a huge advance for All of Us and we are excited about the paediatric work going forward.    Natalie: I love that, how do you come into the future with us? That is fantastic. Naomi.   Naomi: Yeah, if I had to choose one would be the possibility of being able to measure circulating proteins on all half a million participants. We have done this on about 55,000 participants, and just that subset alone is already generating fascinating insights for early biomarkers for disease through protein profiles and risk prediction of disease. I think having that on all half a million coupled with their genomics data and health outcomes, will bring a sea change in how we diagnose disease earlier. So, I think that is a really exciting avenue for us to go into over the next couple of years.   Natalie: Really enriching. That data sounds like a very exciting set of possibilities. Raghib.   Raghib: Thank you. There are so many opportunities here, but I will just maybe mention 3. So, the first, in terms of being able to combine the genetic data that we are collecting and all the other information about risk factors, and particularly the fact that we have this on a lot of young people, will enable us to identify people at high risk of diseases in the presymptomatic phase and then to be able to offer them both feedback about their risk of disease but also interventions that can change their natural incidences. That has never really been possible before. That is extremely important for all diseases for people, but also it is very important for our healthcare system.   So, those of you listening in the UK, I know the NHS is under a huge amount of pressure, and the current model of healthcare which has been in place really since the inception of the NHS, is to treat late-stage disease when people have already developed symptoms and signs. You know, it wasn’t really possible to identify people earlier, but it is now, and Our Future Health will provide the evidence base to show that prevention really is better than cure, and to show that these approaches both lead to better clinical outcomes, but also are cost effective and a good use of resources. Of course, the new government is very much committed to this as well, you know moving from acute care to prevention, from hospitals to community, and from analogue to digital.     Finally, because our cohort has now become so large and does cover every part of the UK, and this wasn’t something I necessarily thought about when we started Our Future Health, we are able to have unique insights into the health of the population across every age group, across every ethnic group, across every geographical area, and by deprivation, and to understand not just observationally in terms of risk factors, but also the impact of interventions on those different populations.   We can look at that, as I said at an individual level on millions of people to gain intelligence about what is going on in terms of public health, but also to see what will hopefully improve their health in the future. So, there are really, you know I have described transformational opportunities to improve health through both biomedical research and populational health insights now through the resource, and I look forward to working with colleagues across the UK and globally to deliver them.   Natalie: We will wrap up there. Thank you so much to our guests, Dr Raghib Ali, Professor Naomi Allen, and Dr Andrea Ramírez for joining me today as we discussed how collaboration, scale, ongoing engagement, can really unlock the potential of large-scale health datasets to drive brilliant new research and ultimately improve the lives of patients and the population.   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, Natalie Banner. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.

In this explainer episode, we’ve asked John Pullinger, Senior Bio Sample Operations Manager at Genomics England, to explain what it means to go on a diagnostic odyssey. 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]. The episodes mentioned in the conversation are linked below. Hope for those with no primary findings The impact of a genetic diagnosis on mental health You can download the transcript or read it below. Florence: What does it mean to go on a diagnostic odyssey? I'm joined by John Pullinger, Senior Bio Sample Operations Manager for Genomics England to find out more. So, John, first of all, can you explain what we mean by diagnostic odyssey?   John: Yes, of course. The diagnostic odyssey is a term used to describe the journey that many people with rare conditions and their families undertake to receive an accurate diagnosis, a journey that takes on average over five and a half years.  The rarity of the condition means that there are few, if any, other people affected by it, for doctors to draw their experience from. Some individuals might never receive a diagnosis.  My job involves making sure that samples sent through the Genomics England processes can travel smoothly from the NHS hospitals to be sequenced and the results be reported back to the individual. We try and minimise the amount of time that samples and associated data is in our care.   Florence: And for people listening who might not know, could you explain why it sometimes takes a long time for people to receive a diagnosis?  John: There are estimated to be over 7,000 rare conditions.  This means that healthcare professionals may not be familiar with all of them and so may not recognise them or know how to test for them. In addition to this, some conditions affect multiple parts of the body. For example, skin, the heart, and the lungs. In these cases, there will be a need to visit specialists from multiple departments, and each will be looking specifically at their own area.  This could lead to referral loops where the patient needs to consult multiple healthcare professionals, all of which contributes to the time taken to receive a diagnosis. Since, for the majority of rare conditions, there is an underlying genetic cause. This means that most individuals who get a diagnosis will receive one through genomic testing, whether that be whole genome sequencing as offered here at Genomics England, or more targeted panel testing.  Typically testing will identify a particular gene, which is known to be linked to a specific condition. For certain conditions, it requires a real expert in the condition to even think about testing for it. Sometimes a condition will present in a way that is different to most other people who have it. So they may have symptoms that others don't. This also adds to the buildup of time taken to receive the diagnosis.  Florence: So, you mentioned earlier, John, that the diagnostic odyssey lasts an average of five and a half years. Can you explain what kind of effect this long waiting time has on individuals and their families?  John: Absolutely. One aspect of the diagnostic odyssey that is important to recognise is the physical effect of the as yet undiagnosed condition that's present and affecting the individual and their family on a daily basis. Those with rare conditions may be affected by a range of emotions connected to the ongoing journey that they're on, including feelings of isolation.  Also stress and anxiety. The fear of unknown can have a massive knock-on effect on the mental health of the individual and their family. And it's important to recognise the signs of this so that people can take steps to manage their mental health. Many rare conditions first present themselves in children and young adults, so considering the effects on their day-to-day lives is especially important.  Florence: If you'd like to learn more about how the diagnostic odyssey can affect someone, listen to our previous podcast, “Hope for those with no primary findings”, where Participant Panel member Lisa Beaton, shares her experience of awaiting a diagnosis for her daughter. And so, John, can we talk now about what happens at the end of a diagnostic odyssey?  John: A section of the odyssey that is essential to understand is potentially getting a diagnosis. It may come as a surprise to think that the diagnosis can sometimes be scary as well as a potential relief to the family and also the individual involved. But this reason the work of genetic counsellors is crucial to help those with rare conditions, understand and adapt to the medical, psychological, and potential reproductive implications of their new diagnosis.   Florence: Our previous podcast, “The impact of a genetic diagnosis on mental health” covers this topic in much more detail. So for my final question today, I wanted to ask whether there are ways that families or individuals affected by rare conditions can access support.  John: We would recommend that anyone who might be going through a diagnostic odyssey who wants to know more about their care to contact their doctor or other healthcare professionals in their genetics team, additional resources are also available online, including the NHS website and charities such as Genetic Alliance UK and SWAN UK.  There are also lots of brilliant patient communities and groups that you can get support from.   Florence: That was John Pullinger explaining what it means to go on a diagnostic odyssey. 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 Genetic Rare Syndromes Observational Cohort (GenROC) study aims to improve our understanding of how rare genetic conditions affect the way children grow, their physical health and their development. Through actively involving parents as experts in their child's condition, the study seeks to gather valuable insights and ensure that family experiences shape future research and care strategies. You can find out more about the study and eligibility criteria via the Bristol University website. In this episode, Jillian Hastings Ward, patient advocate and former Chair of the Participant Panel at Genomics England, is joined by Dr Karen Low, a clinical geneticist leading the study at the University of Bristol, who shares insights into its objectives, the importance of a co-production approach with families, and the vital data being collected in the study to improve support for these children and their families. We'll also hear from Lindsay Randall, a parent who discusses the journey of receiving a rare diagnosis for her child, highlighting the critical need for more comprehensive information and community support. "If you join GenROC, that data will be used to develop a growth chart for your child essentially and their genetic condition, so I’m really excited about it because I feel like that’s a very concrete definite given now for all the families in GenROC, which is just brilliant." You can download the transcript or read it below. Jillian: Welcome to Behind the Genes Lindsay: Historically, there’s been a significant absence of patient voice in rare disease research and development, and knowing that’s changing, I think that’s really empowering for families and to know that professionals and industry are actually listening to our stories and unmet needs and really trying to understand, and that offers much greater impact on the care and treatments of patients in the future. Jillian: My name is Jillian Hastings-Ward. On today’s episode I’m joined by Dr Karen Low, Consultant Clinical Geneticist and Chief Investigator for the General Cohort Study, and Lindsay Randall, Paediatric Practice Development Nurse and founder of Arthur’s Quest, which is a UK registered, non-profit, raising awareness for the ultra-rare condition: SLC6A1, developmental and epileptic encephalopathy. Welcome to you both. Today we’ll be discussing the GenROC study, which is aiming to understand more about the health, development and valuing the experiences of children with neurodevelopmental conditions. If you enjoy today’s episode we’d love your support. Please like, share, and rate us on wherever you listen to your podcasts. Thank you both very much for joining us today, Karen and Lindsay. There’s a lot we want to cover, but first of all it would be great just to put a little bit of context around the Gen-Roc study. Karen, can you tell us a bit about what the study is aiming to do, who is eligible and why do you want them? Karen:  Thank you. And thank you so much for having me today, Jillian. So, the GenROC study, first to just explain to people what ‘GenROC’ stands for. GenROC stands for the Genetic Rare Syndromes Observational Cohort Study. Just to give you some context about the study, I’m a clinical geneticist and most of my clinical work focuses on paediatrics, so I see children in my clinics and the sort of children I see generally are children with rare genetic syndromes. The last five to ten years we’ve got much better at diagnosing children with these rare conditions and that’s because testing has got so much better. We can now do whole genome sequencing and we can do that on the NHS, which is amazing, children can get their tests as part of their clinical care, so it means that a lot more children are being diagnosed with rare conditions, about 2,000 per year in the UK. And the thing about that is, that I see these children in my clinics and I give their families that diagnosis. But the problem is for so many of these ultra-rare conditions, like Lindsay’s family has, we sit there and we say to the family, “Well, your child has got ‘X’ condition,” and we give them some information from maybe one or two publications and linked to a leaflet and a Facebook group. And then we say, “But really we don’t know that much about this condition.” And they say, “But what is it going to mean for them when they are growing up or when they are adults? Will they be able to finish school? Will they be able to work? What is it going to mean?” And I have to shrug my shoulders and go, “I’m not really sure.” And as a geneticist and as a doctor and as a mother really, I just felt that wasn’t good enough, and I found it really frustrating and I know that the families that I work with, that I look after, also find it frustrating and I wanted to do better. And I also found it frustrating that for many genes, researchers would publish two or maybe three publications about these conditions, and then they would move on to the next novel gene, and actually, the journals are a bit like that as well, they like novel things, they like new conditions, they like the next gene. And so, it means that actually data doesn’t always carry on being gathered in these rare conditions, and there are a lot of them. That was another thing, I sort of felt that these conditions were being done a disservice and that we needed to do better, so that’s where the whole idea of the GenROC study came from was my drive and desire to improve things for families and actually to work with families to improve that, and that’s where so this is a very highly co-produced study and right from the outset I’ve involved parents in telling me what they wanted to know and I’ve got a very, very active PPI group, full of parents of children who have got rare genetic conditions, and also I’m really lucky to have a young adult who has a genetic neurodevelopmental disorder herself and they all tell me about essentially what I should do and what I shouldn’t do. They tell me when I’m not doing enough or when I need to do something differently, so it’s very highly co-produced, they’re highly involved all along the way. So, children with a confirmed genetic diagnosis in a list of eligible genes which people can see on our website if they Google GenROC University of Bristol, we’ve got a very easy checker for eligible genes, but they are essentially the most frequently diagnosed genes in rare neurodevelopmental disorders. And if their child is under 16, has a confirmed diagnosis and doesn’t have any other genetic diagnoses then they can go into the GenROC study, that’s essentially the eligibility criteria. Jillian: That’s really interesting. It’s very helpful to hear the background and I think as a parent of a child with a very rare disorder hearing that the clinicians also recognise this gap and the sort of pause that happens once you have your initial diagnosis, is really helpful and really encouraging. Lindsay, can we turn to you next and can you unpack a little bit about what it meant for you to get a rare diagnosis for your child and what point on your family journey was that compared to where you are now? Lindsay: I think to get a rare diagnosis for us was difficult and challenging and I think the first kind of challenge that any family has is actually being well-informed by a paediatrician who is also well-informed, and that’s not always the case. That can affect the way we acknowledge or accept a diagnosis and how we also access support and how we understand what more we can do to make more connections. We did have genetic counselling offered, but I think there are families out there who don’t get genetic counselling offered to help them understand the child’s diagnosis, and then there’s a heavy reliance on the internet, and as you said, there’s a lack of information out of there. A lot of conditions are newly diagnosed or they’re very complicated genes to work with, or as Karen said, they’ve had a couple of papers and people have moved on. And I think that does cause an immense feeling of isolation. We were diagnosed in 2018, our son, our first child, and exactly as Karen said, it was a fairly quick appointment of, “We don’t really know much about this condition at the moment, there’s a couple of papers. We know of 34 children in the world at the moment with your condition. Here’s a Facebook group,” which we did join. And it is overwhelming to be given a diagnosis that’s delivered with such little hope I guess, finding sources of information that’s valid and robust is challenging, not everyone knows how to do that or has a skillset to conduct searches of academic research and I think that clinicians could definitely do better in also signposting the kind of umbrella charities like Unique and Contact and Swan and patient organisations, because I know that would have been definitely helpful for us as a family to be able to have opportunities to connect with others. Jillian: Thank you. Our diagnostic journey has been a bit a similar in that we were diagnosed through the NHS, and that at the time my son was the first person diagnosed with his disorder in the whole of the UK so it was really a big question mark, it was a question of our geneticist saying, “Here’s the three PDF articles that we know exist in the world about this condition. Can you read them and tell us whether you think that sounds like him in order for us to be confirming our diagnosis?” I very much hear what you’re saying there about feeling lost in the wilderness. And we too joined a Facebook group quite shortly after we got our diagnosis, and at the time my son was among the older ones or certainly as time has gone by he has been among the older children, so it can be really hard to know what might happen next. I think that now as Karen was saying we’re getting much better at diagnosing people thanks to all the extra testing that’s happening, that happens much earlier in life than it has done in the past, but I think then it still leaves a gap in parents’ understanding because you don’t necessarily know what the next ten years might look like for example. And so, I think making connections with people who are in that age bracket can be really important, but it’s very hard to do. So Lindsay, I’m conscious that your professional training as a nurse must have stood you in quite good stead when you were faced with a barrage of medical literature shortly after your diagnosis, but I think one thing that every parent shares is the desire to do the best for their child and especially in this world of rare disorders. There’s a huge amount of energy that comes through the community I think, faced with the need to try and self-start and build these networks and connections for themselves. Is that something that you’ve seen in your community as your experience? Lindsay: Yes, definitely. I think we’re a growing community and over the years of course more and more children and young adults have been diagnosed with a few older adults coming through. It is very much a global networking effort and parent/patient organisations have been set up in many countries now by parents of children with children with SLC6A1. I definitely think that drive to become an expert in your child’s condition is a long journey and one of continual learning and actually a lot of families simply don’t have a capacity to take that on, I think often the medical and scientific jargon is difficult to understand and that makes it challenging to access. And as you said, as a paediatric nurse, I at least have some existing skills to understand healthcare to read the research and speak with medical and scientific professionals with some confidence, but in some ways, that has increased the burden I’ve placed on myself to become an expert for my children and other children and families who are not in the same position as me. It does require a lot of dedication and time, and that does have implications on families because it’s time away from our children and from home, and from the remnants of our lives that we desperately try to cling onto, to not lose all sense of ourselves. It’s not often spoken about but I do see the strain it places on the families, as well where there’s a lot of separation and divorce sadly in the rare disease communities, and often that’s as a result of one parent’s drive to be the expert, which seems to cause one parent to fulfil more burden of care and that fosters some level of resentment or sense of loneliness towards the other one. Jillian: There are some scary statistics out there around familial breakdown in this context, and it is something which there are so many factors at play, but it definitely seems to be quite widely recognised and definitely a problem. In terms of the time that people have to spend on liaisons with the research community and the clinical community, that could bring us quite nicely back into a question for you, Karen, about what kind of information the GenROC study is looking to collect from families, can you tell us a bit more about that, please? Karen: Yes, absolutely. As I said before, I’ve been very conscious of the sort of lives that our families are living, and listening to Lindsay, her story is very reminiscent of so many others and yours, Jillian. So I know families have about a gazillion hospital appointments, their children are often also very, very ill intermittently or a lot of the time, then they’ve got school stuff to deal with or they’ve got EHC plans to try and fight for. It’s more than a fulltime job in itself just being a parent of a child with a rare disease and it’s hard work, so me asking them to do anything else is asking a lot. Luckily, I find, with the families I work with, who are universally wonderful I should add, that they are actually just really enthusiastic anyway about research for their child’s condition, and that’s because there isn’t enough information out there, so it’s relevant and important to them. But because they have no time at all, and any time they do give is their own personal time when they could be finally putting their feet up and watching something on TV, I have to make it as low effort as possible. The questionnaire is all online, using a user-friendly and interface as we’ve been able to develop. It’s very user-friendly, it takes 10-15 minutes to complete; they can come and go from the questionnaire as well. We only ask for one time point at the beginning, which is all the sort of stuff that most parents will be able to tell you off the top of their head as well, so they don’t have to go looking for loads of information, apart from a height and a weight. Then later down the line we’re going to ask for a second questionnaire, it’s in the process of being finalised and again that will be the same amount of time, very easy to do, online, at their convenience. It was co-produced with the PPI group, they’ve tested it for me, I’ve had really good feedback and I’ve asked parents who are in the study as well for feedback. Everyone tells me it’s not too difficult or burdensome for them to do. The secondary questionnaire has been very much informed by conversations with the parents that I had as part of a nest of qualitative interview study in GenROC, and that has driven that secondary questionnaire quite differently to what I thought it might be when we first set up the GenROC study. At the beginning I thought it might just be: have things changed for your child? Can you give us a bit more clinical data? But actually I realised that probably I will still gather that information, but they probably won’t have changed that much within the timespan in the study because it will only be a year or two after they completed the first questionnaire, and actually I realised that it would be much more useful to look at the impact of the genetic diagnosis, look at how they’re accessing services within the NHS, what sorts of services they are accessing, Impact on the family and also looking at priorities for families. So families have talked to me about what their priorities are in rare disease, both in service provision but also in research, and I really am a very strong believer that we need to be given the limited funding, we need to be doing the research that matters the most to the families, not to the researchers. What do families actually want us to look into? Actually, do they want us to be looking into behaviour and what strategies work best for example, rather than something else very medical – what matters the most? And so that’s going to be a specific question in that secondary questionnaire, really trying to identify what matters to families the most and then how that can be translated into clinical research in the future. So I’m really interested to see what’s going to come out of that. Lindsay: I think that sounds brilliant, Karen because I think historically there’s been a significant kind of absence of patient voice in rare disease research and development, and knowing that that’s changing, I think that’s really empowering for families and to know that professionals and industry are actually listening to our stories and unmet needs, and really trying to understand, and that offers a much greater impact on the care and treatments for patients in the future and certainly it makes endpoints more relevant to families as well. Jillian: What kind of outputs are you going to be looking at? Karen: The height and weight, the reason I’m asking for that is really because we are trying to work on growth charts for children and that’s because growth charts for children with rare conditions don’t exist by enlarge, there are a very, very tiny number of rare syndromes or conditions that have their own growth chart. The problem is that most children with these sort of rare conditions that we’re talking about are either quite small or quite big, and the problem is that the paediatricians look at their growth and they go, “Oh well, you’re much bigger or much smaller than other children your own age, what shall we do about that?” and particularly the little tiny ones it causes lots and lots of concern, so quite often these sort of growth parameters mean that the paediatricians do lots and lots of tests or put feeding tubes down, or add lots of calories, so it can be quite invasive and interventional actually that sort of growth parameter. But actually, sometimes that’s because of the genetic condition and no matter how much feeding you do it’s not going to change anything. The difficulty is we don’t know that for certain, and actually we need good growth charts where paediatricians can make that call, and conversely sometimes a child actually does need investigating and the paediatrician puts it all down to their genetic condition, and that’s why we need these growth charts. So GenROC is aiming to gather growth data from all these children and then we’re going to work closely with Decipher, which is a website that was developed through the DDD study, which already holds lots of data from that study, so we’re building on the power of that study and we’re going to be generating growth charts for all of these genes. We’ve developed a new method for producing growth charts for rare conditions where you’ve got small numbers of patients – that was never possible before, so we’ve already proven now for four conditions we can, so the next stage is using all the GenROC data, putting it into Decipher and coding it in. So, if you join GenROC, that data will be used to develop a growth chart for your child essentially and their genetic condition, so I’m really excited about it because I feel like that’s a very concrete definite given now for all the families in GenROC, which is just brilliant. Jillian: And is that something which will be shared with the families individually? Karen: Really great question. I hadn’t planned on sharing the growth charts individually with the families, but that’s something I can also go back to my PPI group and discuss with them about whether that’s something people would want, and also I have a newsletter which goes out every three months to the families, so I can certainly ask that question actually directly. It’s going to be widely available, the growth charts, we’re going to make sure that they’re accessible to paediatricians and clinicians etc. but in terms of output to the study, definitely the growth charts, we’re also hoping to have other clinically useful outcomes depending on the different genes that come into the study. We essentially have a cohort of children with rare conditions, everyone puts everything down to a specific genetic condition but we know that there must be other factors at play that influence how children do. And this is a really unique thing we’re trying to do with GenROC actually, looking at aside from that genetic variant, that alteration, what other factors are influencing how children are doing? Because some of those might be modifiable, you know, or some of them there could be things that could be put in place to help improve outcomes. So I’m quite excited about that as well, because that’s quite new and novel and not really been thought about in this context before, so that will be an output. And the other output is something that I’m working on with Unique, which is the rare disease charity who has worked with us on GenROC from the start, and they are involved in our PPI as well and that is going to be looking at a template, calling it a report at the moment, it’s in very early days, but something that parents will be able to hold, it’s going to have lots of drop-down boxes that can be tailored and modified for individual patients and children, which will be a bit of a guide that they can give to clinicians, professionals, education, telling them about their condition but also telling them on an individualised basis about what needs to be looked for in the future. Because parents tell me they are fed up of having to tell everybody about their child’s condition constantly, all the time, over and over again. So what the point of this output would be is to try and ease that burden a little bit. This is very early stages but we’re going to involved parents all along the way. Jillian: And is that something which builds on the hospital passport idea that we’ve seen emerging around the world over the last few years where parents can start off telling their child’s story on their own behalf? Karen: So, it’s come from my own lived personal experience of being a mother of a child with autism and I haven’t really spoken about that publicly before, so it’s something I’m saying for the first time. I have a child who has autism and I have had to navigate things like a DLA application form. Jillian: That’s Disability Living Allowance. Karen: Yes, exactly, which is a horrendous form, it’s the most horrible form to complete, probably apart from an EHCP plan form but it’s a horrible form to complete, it’s quite upsetting as a parent and it’s also got millions of boxes that you have to fill in. But one of the things that really, really helped me when I was completing that was a charity who had come up with lots of drop-downs that you could select from that might be applicable to your child to help you complete this form. And so it made me really think, “Well, could we do something similar for our children with genetic conditions but come up with lots of dropdown options that might apply to their child in all sorts of different areas?” And that was the inspiration, it was that, and doing the qualitative study that I’ve already done with parents of children in GenROC who were telling me about how fed up they were of having to constantly tell everybody about their child’s condition over and over again. Jillian: Yes, that’s probably very helpful to empower families to use standard terminology across the different families because my own son has epilepsy as part of his condition but actually trying to describe what his seizures look like I’m not sure I’m using the right words to fit the right boxes to fit them into the right categories with the neurologist. So that level of standardisation is something that we definitely need embedded into the system in order for more people to be able to use this data more effectively, so that sounds very helpful. Lindsay, coming back to you, what are you hoping to get out of this study, or what are you hoping this study will do on your behalf for the world? What motivated you to take part? Lindsay: I think I would like to see all of the aims of the study realised and for the study data to be used to inform the development of standards of care for a wide range of conditions, those included in the study. I think it would be great if that information, as Karen said, is available not only to the participants but also to children diagnosed with those conditions in the future and also it’s an opportunity to consider themes that are identified across the disease groups as that can also help inform future research and look at investigations into the mechanisms of disease and where actually therapeutics could treat maybe more than one disease at a time and increase potential for basket trials and early access programmes – thank you to Dr Karen Low and her team for conducting the project because it included a comprehensive list of rare diseases, it really does give parents and patients an opportunity to have a voice and to contribute, which is empowering, and it gives them a little bit of autonomy as well over their direction that science and research goes to. Jillian: Fantastic, thank you. Karen, can you tell us a little bit about the timeframe for the study? I realise that we haven’t really touched on that so far. Karen: Yes absolutely, I’m aiming to recruit 500 children as a total. We’re open at 22 sites across the UK. Coinciding with this podcast actually we’ve opened a second door for recruitment, so the way we’ve recruited so far has been through clinical genetic sites, which is the way we’ve done these sorts of studies in the past, like the DDD study. The problem is that that relies on clinicians identifying eligible patients and clinicians are very, very busy in the NHS. I have worked closely with Unique who have been doing a lot of publicity and the genetic alliance have done publicity as well for the study, so that’s been one way of identifying eligible participants. And also just parent power through social media has been amazing. The second way we’re going to recruit, and this is going to happen very soon, is through Genomics England. So, we are going to trial a completely novel way of recruiting to research through Genomics England and that is for Genomics England to identify eligible participants for GenROC and this would have been through the 100,000 genome study and then they’re going to send them invite letters, inviting them to take part. So that’s the next phase of recruitment, I think if we have more than 500 then that will be great too, we’ll be able to include those comers too, so that’s not a problem. But we don’t know whether this will work or not in terms of a way of recruiting to research, this is completely new for Genomics England and I’m a bit of a guinea pig if you like through the GenROC study, but I was quite willing to be that guinea pig because I thought it might increase access. So there will be some parents who have not been told about GenROC who have not heard about it, and who would love to take part, so I feel like this is the way of really widening that net as wide as possible. Jillian: I think that is a challenge isn’t it, especially in rare disease – there’s no point doing a public broadcast about an initiative because you’re going to hit so few of the people that you’re interested in, so actually how you access the community is the first challenge and I’m really pleased that Genomics England will be able to help you there because I think that is a very useful route through. I think it will probably be quite reassuring to quite a lot of families who were on the 100,000 Genomes Project who have got a diagnosis of one of the conditions that you’re interested in, and are now perhaps subsequently in the fallow period after you have a diagnosis, wondering what happens next, so I can imagine it might be quite good news for some of them at least that they are now being invited to do something further. And the reason that you’re building forward and you don’t want people who are currently in the deciphering developmental disorders study is because you’re already using their data through another source, is that correct? Karen: Exactly. So absolutely, I don’t want anyone to feel that I don’t want them, that’s really not the case. I do want them but we have their data already from Decipher, so we’re building on the DDD data already, so they’re already contributing which is just the beauty of it, because that’s what we should be doing in rare disease, we should be building on previous research because you know, you don’t want to be trying to reinvent the wheel. Jillian: Agreed. So if someone is listening to this and has a child with a rare developmental disorder and they are interested in finding out more, what are the steps they need to take? Karen: If they Google Bristol University, GenROC, they’ll come straight to the webpage and everything is on there. There’s a link that they can sign up, the patient information leaflet’s there, the eligible gene list is there, all the information they need, including our email address. Jillian: And is there an upper age limit for recruitment? Karen: Yes, children have to be under 16 and that’s because once they get to 16 many of these conditions have associated learning difficulties, and it’s just very much more complex to try and recruit young adults, young people, with learning difficulties and given it was a cohort study we felt it was going to be too difficult at the moment. Saying that, I have a huge interest actually in how these conditions present in adulthood, and I’m actually conducting a much smaller study at the moment in KBG syndrome, looking at adults, and so I hope that my future research career will allow me both to follow-up the children in GenROC, so that would be my vision but also to be able to take this forward for other adults with rare conditions, that’s my aim and goal in the medium to long-term, so watch this space for that. Jillian: That sounds very exciting, thank you. Lindsay: I think I would like to say to Karen that I really like the sound of the idea of following patients up into young adulthood and adulthood, as you said, that is definitely a kind of an unknown area in lots of the rare diseases, especially in our condition, SLC6A1, it was mutation and the disease was only really discovered in 2015, so it is fairly new and we have very, very few young people and adults coming through and being diagnosed and connecting with the rest of the community. So, being able to understand the trajectory of conditions better and especially conditions where actually the presentation it’s quite a spectrum, and so the long-term outcomes for people with SLC6A1 can look quite different, so it’s good to collate more information about that I think. Karen: I think it’s really important, so that’s definitely where I’m looking to for the future with GenROC and more widely, I think it’s just something I’m really interested in and has huge relevance for parents and families. Jillian: Well, I think we need to wrap up there but thank you both very much Dr Karen Low and Lindsay Randall for joining me today as we’ve been discussing the GenROC study, and how the study aims to improve understanding of how rare genetic syndromes affect the way children grow, their physical health, their development, but also how the patient and parent communities can work more closely with researchers to end up delivering something which is of a huge benefit to everybody. If you would like to hear more about this, please subscribe to ‘Behind the Genes’ on your favourite podcast app. Thank you for listening. I’ve been your host, Jillian Hastings Ward. This podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.

As 2024 comes to a close, we take a moment to reflect on what has been a busy year at Genomics England and in the wider genomics community. Throughout the year, guests have joined us to discuss groundbreaking research discoveries, important ethical considerations, and share their personal stories. It was also a year of transformation: we rebranded our podcast as Behind the Genes, welcomed Dr Rich Scott as our new Chief Executive Officer, and launched the Generation Study, in partnership with NHS England. The Participant Panel also saw changes, with Kirsty Irvine stepping into the role of Chair and Adam Clatworthy and Helen White becoming Vice Chairs. In this special end of year episode, Adam Clatworthy, Vice-Chair of the Participant Panel, sits down with Dr. Rich Scott, CEO of Genomics England, to look back on the highlights of 2024. Together, they revisit key podcast moments, reflect on research discoveries, and share insights into the evolving world of genomics. Below are the links to the podcasts mentioned in this episode, in order of appearance: Celebrating genomic breakthroughs - Insights from the Festival of Genomics Shining a light on rare conditions How has a groundbreaking genomic discovery impacted thousands worldwide? How can we work in partnership towards a new era of genomic medicine and research? How has design research shaped the Generation Study? How can we bridge the gap between diverse communities? Can Artificial Intelligence accelerate the impact of genomics? "It's really important that we just continue to bring that patient and participant community on that journey, just to ensure that they really understand the full benefits. And we've talked about that on the episode today. I know that the panel has always encouraged the Genomics England team to look at its boots while shooting for the moon. I really like that phrase just to make sure, look, we can't forget where we've come from to make sure we're taking people on that journey" You can download the transcript or read it below. Adam: Welcome to Behind the Genes.  Rich: Our vision at Genomics England is a world where everyone can benefit from genomic healthcare, thinking about how we ensure the lessons we’ve learnt through our diverse data programme is embedded across all of our work.  So that word “everyone” applies to people in lots of different ways, different communities people come from, different socioeconomic backgrounds, making sure that equity is baked into all of our work.  And there’s real opportunity for genomics to play a broader role than in rare conditions and in cancer, we’re proud of the impact we’re already having there, and we should really look to the future.  Adam: My name is Adam Clatworthy, and I’m the Vice-Chair for rare conditions on the Participant Panel at Genomics England.  On today’s episode, I’m going to be joined by Rich Scott, CEO of Genomics England.  We’re going to be taking a look back at the key milestones from 2024 for Genomics England, and really discussing our hopes and aspirations for the year ahead.  During this episode we’ll also hear from some of our guests we’ve had on the show this year, who have helped shape our discussions and shared some of their most impactful moments and insights.  And if you’d like to listen to more like this, then please subscribe to Behind the Genes on your favourite podcast app.  So, with that, thanks for joining me, Rich, how are you doing?  Rich: I’m great, thanks for hosting today, I’m really excited about it.    Adam: So, Rich, it’s been a pretty exciting year for you, you’ve taken on the CEO role at Genomics England full-time, so why don’t you just start by telling us about how those first few months have been for you?  Rich: It’s been a really exciting year, I think for us overall at Genomics England, and obviously personally taking on the CEO role, which is an enormous privilege.  I’ve been at Genomics England nine years, and I think both a privilege and a real responsibility to take on the role.  To think both about how we continue to honour the commitments we’ve given our participants and those we work with, and to think about the future, where we might go together, what evidence we need to generate, what our systems need to support.  So it’s been great taking on the role, and thinking about that, both the present and the future, and there’s been lots, as we’ll talk about, there’s been lots going on.  Adam: No, that’s great.  And I must say for myself as well, I started the Vice-Chair role at a very similar time to you early in the year.  When I started, we were in the process of looking for our next Chair.  Obviously, we had Jillian and Rebecca, both standing down, after many years in the role.  They’ve been there from the start, really guiding the Panel through this amazingly successful period.  But for me, I’ve really enjoyed working in partnership with Helen, who is our Vice-Chair for cancer.  It’s been a real partnership, in terms of filling in for that interim leadership role.  And we wanted to make sure that we weren’t just caretakers, we were really continuing to be actively involved in a lot of the discussions that are happening with your colleagues across Genomics England.  Very much leading the Panel, and starting to have those important discussions around, where does the Panel go next?  And what’s our strategy for the next two to three years?  What are the key areas that we can drive real value and impact, in line with your own milestones at Genomics England?    And, of course, I’ve just loved getting stuck into chairing the Panel meetings as well, for me, that’s the best part, is really bringing together these amazingly diverse and passionate people.  With so many different personalities, lived experiences, and a combined passion for just taking this forward together, and making sure that the benefits of genomics really impact, and that’s felt by the wider community itself.  So there’s been lots of highlights to recognise this year, a real stand-out for me has to be the Genomics England Research Summit, from what I understand it was the most attended event to date.  And it was just so good to see that a lot of the Panel were front and centre across that event, sharing their stories, having a really active role, whether introducing speakers, or telling their own journeys as part of the Q&A sessions.   I myself was really privileged to be on stage with Baroness Nicola Blackwood, literally nine days after I officially started the role.  So it was great to just dive in at the deep end, get in front of an incredible audience, and just see that the broader Panel was front and centre of the event itself.  And it was just great to see how popular the event was, many more people coming to have a chat to us on the stand than would have found us before, so, all in all, a really big highlight for myself.  So, for you, Rich, are there any other highlights that you want to call out for this year?  Rich: And first to say, absolutely agree with the Research Summit being, you know, a highlight.  The diversity of the discussions that we had, it’s one of the things we enjoy most about thinking about creating the summit, as you say, involving the participants very much at the centre.  Like, physically at the centre of the room, for people to come and talk to participants and hearing stories.  And then really seeing how over the years we can see the impact growing, and having talks, whether it’s about individual findings, or big research studies.  So the final talk of the day was from Charlie Swanton.  He was talking about some really exciting work that his team have done in our National Genomics Research Library, making a really important discovery about extra chromosomal DNA in cancer, and that’s now been published in Nature.  And then right next to him, we were having a policy talk from Sam, who’s the CEO of NICE.  And you can see the range of things, the sorts of evidence, sorts of conversation, we need to have, so that was really fantastic.  I’d call out one discovery this year that maybe we’ll come back to, and one other big highlight.  So I think the big discovery this year was the discovery of this piece of non-coding sequence in the genome called RNU4-2, which turns out to be pretty much the most common cause of developmental disorders that’s been discovered.  And it’s just so exciting to see that having been discovered in the National Genomics Research Library.  And then the news, the knowledge spread, across the world, and family support groups coming together to understand and learn more about what that means for them.  So that was, I think, the discovery over the years at Genomics England that’s touched me most, seeing that story.  And I’d say for us, organisationally, another big highlight has been the launch of our newborns programme, the Generation Study.  So as lots of people listening will know, we’ve been actually thinking about what the questions underlying this study are for a good number of years, doing a lot of preparatory work.  Actually, before we even started, setting up public dialogue jointly with the National Screening Committee about what the public were keen to understand and the appetite for research in this area.  And then we’ve been spending several years designing the study, working with the NHS how to design, safely launch it, National Screening Committee involved all along, and working with patients and the public to design it.  And this year now launching the study at a public launch, just a couple of months ago, by the time people are listening to this, and at the time of recording, more than 2,000 families have joined the programme.    So really exciting, us exploring a really big question for genomics, about the use of whole genome sequencing in newborn babies.  Whether that should be offered to every baby at birth, primarily driven by that desire to do better for those children born with treatable conditions, where genetics, genomics, can be a way in to finding them, but doing that at the right pace, and very much in a research setting.  That’s been a real, a moment, I think there’s been so much work on the path to it, but it’s right to sort of celebrate these staging posts on the way.  We’re early in the programme, there’s lots to do, lots to work through, lots of evidence that we’ll accrue, but it’s really exciting to be at that staging post.  Adam: No, absolutely, and from my side, I think seeing all of the media pick up for the Generation Study launch, you could really see the excitement in the wider kind of community.  Seeing it shared on social media, obviously those part of the 100,000 Genomes Project, seeing things like this.  It’s like they can see the tangible outcomes of all the work that they’ve done as part of that initial project, and seeing how those learnings are then taken onto this new study.  So we’ll now hear a clip from earlier in the year from Louise Fish, who is the former CEO of Genetic Alliance UK, who shares her thoughts on the potential of the Generation Study.  Louise: The Generation Study is looking at 200 conditions and whether it’s possible to screen for them.  And for all of those 200 conditions, it’s a really exciting opportunity to see if we can learn more.  Both about the potential to understand and develop treatments early, but also just about the chance to understand the natural history of that condition so much earlier than we do at the moment.  And I think that’s it, it’s that understanding the natural history of the condition really early, and understanding how a family can be helped, through all aspects of the condition, which is giving people most excitement I think, alongside the potential to develop treatments.  Adam: So now, let’s look back at the priorities for Genomics England for 2025.  Now, Rich, would you like to just take us through some of the things you’ll be focusing on next year?  Rich: Yes, one of the things that we’ve been doing this year, but also actually in the year before, is really looking to the future.  And saying, where might we be in terms of genomics really living up to the impact it could have, if we collectively, in the UK and working with international partners, sort of get things right?  And that’s very much about balancing the realism of where we are, and the impact we’re already having, and being proud of that, and then getting that same sort of ambition and realism casting to the future.  And I’d say, I think there are two really broad themes.  I think the first thing is, we’re enormously proud of the impact we’ve had already for families with rare conditions, and people with cancer, and that impact will continue to grow in the coming years, in those areas.  And in the next few years, that’s where the biggest impact of genomics will continue, and the rare disease programme we have thinking increasingly about how we support the generation of evidence and pathways that lead to rare therapies.    So building, getting better all the time at finding diagnoses, which is still a long journey we’re on, and continuing that work.  Increasingly thinking about how we can support therapies, and in cancer, again, playing a better role in cancer, both by driving efficiency in diagnostics, and efficiency in identifying where therapies enabled by genomics can be targeted.  And we see lots of different examples of that, clinical trials is a big area where we hope to have more impact in the future, but also thinking about some of the novel therapies that are there, both for rare conditions, but also, for example, the cancer vaccines.  And I think we’re uniquely placed in the UK, because of our partnership at Genomics England with the NHS, and the broader science ecosystem, to have that impact.  So that’s the sort of like continuing very much where we are, but really pushing those boundaries.  And then also, if we look to the future, to say, what role could genomics play?  And we, as you know, our vision at Genomics England is a world that everyone can benefit from genomic healthcare, and I think that plays out in a couple of ways.  Firstly, thinking about how we ensure the lessons we’ve learnt through our diverse data programme is embedded across all of our work, so that word “everyone” applies to people in lots of different ways, different communities people come from, different socioeconomic backgrounds, making sure that equity is based into all of our work.  And then also, to say there’s real opportunity for genomics to play a broader role than in rare conditions and in cancer, we’re proud of the impact we’re already having there, and we should really look to the future.  And as we set out where we think what evidence is needed and where we need to learn what the digital infrastructure that we build and others build, need to build that to support that, we look across a few different areas.  But really you can see genomics playing a role across the lifetime, in different places in different roles.   To pick one really powerful example is something people often refer to as pharmacogenomics.  Which is a medical term for what boils down to look at a person’s DNA sequence, that’s the genomics bit, and making decisions based on what drug to give them, what drugs to avoid, or perhaps what dose to drug to give them.  Based on, for example, the desire to avoid adverse drug reactions that people might be at high risk of, and you can identify that risk looking at the DNA.  That is one example of genomics playing a role in being increasingly sort of preventive, getting away from disease, getting upstream of disease arising, or harm arising.  And there are other opportunities in common disease as well, sort of casting forward to what that impact might be, and we feel that genomics could play a role, really broadly, across healthcare, in probably as many as half of all healthcare encounters.    But what we need to do over the coming years for that to potentially be the case is we need to build out the evidence, and we also need to understand what digital infrastructure we need, to make that a possibility.  So that the information is there in simple format, for patients and the public, for their GPs, for their pharmacist, for people in any speciality in hospital, not just sort of rare disease clinics or in cancer, as we are at the moment.  And so very much we’re thinking about the programmes that we and others could run to ask some of those questions, to think about what we need to build out.  We feel that the UK’s uniquely placed to develop that evidence, so that we can make the choices about how genomics is used, and so we can be ready to embed it.    And it really aligns with that shift that we see and we hear, for example, in government being talked about, when we’re looking about sort of the shifts that the NHS sees as essential.  You know, increasingly preventive, increasingly digital, increasingly in the community, and that point of sort of getting upstream.  And genomics is going to be an important part of that.  And we at Genomics England are really excited about the role that we can play, whether it’s through the digital infrastructure we build, whether it’s the programmes that we run to develop the evidence.  Or whether it’s through the ethics and the engagement work, the work with the Panel, and the work with the wider public, to understand how we might develop this evidence, what people are comfortable with, what the expectations are.  And I think that, pulling that together is complex, it’s really exciting to think about how we do it.  I think we in the UK are uniquely placed to take advantage of that.  Adam: That’s great, and I think the pharmacogenomics piece is fascinating.  I mean, you hear many stories of people having adverse reactions to certain medications, and you wouldn’t even think it’s something that may be linked to their genetic makeup.  It’s so important that we take people along that journey, around what the benefits are, the ethics, to make sure that people really understand the journey that we’re making and what the potential impact could be.  Whilst there’s lots of amazing new areas to develop into, a key focus for us on the Panel is really continuing to demonstrate how the 100,000 Genomes Project participants continue to have an impact, and they’re helping shape a lot of these developments.  So they generously donated their data, it not only helps Genomics England develop the systems and services that now benefit many families, but it also continues to drive that scientific and technological enhancement.  So it wasn’t just about reaching that 100,000 genomes, that project was really the starting point, as it were, it’s not the finish line, it laid the groundwork for a lot of these developments.  So it’s about how do we focus on maximising the benefit for those participants over their lifetime, not just at that one point in time.    We know genomics is evolving so rapidly, what you can glean from a genome today is far more than what was possible in 2013.  And we know the Diagnostic Discovery team is continuing to analyse the data for participants in the project based on these new advances, the team led by Suzi (Walker), who’s doing some amazing work there.  Using all the latest tools and enhancements, just to make sure that those participants are really benefiting from that learning.  So, we just need to make sure we stay close to that wider community, and just ensure they’re not forgotten, that’s really a key north star for us as the Panel.  And something that we’ve been pushing is better ways that we can help to communicate the ways that you're celebrating these successes, providing regular updates on research progress, offering personalised reports based on the latest findings.  And it’s all about providing them with that hope.  Some people may never get a diagnosis, but it’s about giving the hope that one day they might get that phone call out of the blue, so it’s about giving the hope that those possibilities are out there for others.    So we’re now going to shift gear onto hearing from Shaun Pye, who is the father of Joey.  She was diagnosed with DYRK1A syndrome, which is a rare chromosomal disorder, which causes a degree of developmental delay or learning difficulty, at the age of just thirteen.  In this podcast episode, Shaun and his wife Sarah told us of their journey to Joey’s diagnosis, and how their role in writing the BBC television comedy drama series, There She Goes, has helped to shine a light on the rare condition community.  Shaun: Then the opportunity came along with 100,000 Genomes, and we signed up immediately.  And then that, they did that, and it was a few years before that went through the system, and then we had, out of the blue really, we were asked to go and see a geneticist, and we had no idea that this is what it was.  I honestly thought it was just a routine sort of, we’ve got a few more theories or something, and she just said, “We’ve found out what it is.”  And it’s like, that moment is, well, we tried to describe it in the TV programme, but it is quite hard to describe what goes through your mind, when after thirteen and a half years somebody suddenly says, “Oh, by the way, that thing that happened with your daughter, we’ve worked out what it is.”  Adam: So here, Rich, did you want to provide some updates around future progress, particularly in diagnostic discovery and expanding the research?  Rich: When we’re looking to the future, we’re looking sort of in two areas.  How we can build the impact we’re having today for families with rare conditions and cancer, and that very much includes the participants in our programmes, 100,000 Genomes, those through the NHS Genomic Medicine Service, who joined the National Genomic Research Library.  And we’ve seen, I think the number that I’m most proud of at Genomics England is that number of diagnostic discoveries returned to the NHS, which has just hit the 4,000 mark.  And for those less familiar with the terminology, essentially what that means is where either researchers or the internal team at Genomics England have identified changes in the genome data, that with new knowledge, often with a fine tooth comb, it’s considered likely that that is the answer to the cause of the rare condition in that person in the programme.  So that’s 4,000 of those returned to the NHS.    And that tells you a lot about where we are for families with rare conditions, and I think there’s two points here.  The first one is, we’ve got a long way still to go to do what we want to for families with rare conditions.  I’m a doctor and still see families in my clinic once a month at Great Ormond Street, even with the incredible advances we’ve had over the last particularly 10or 15 years, with the changes in sequencing and analysis, we still find an answer for the minority of families.  So that number is growing, and we’re really proud of how much better we’ve done, and there’s a long way left to go.  And the really critical thing is designing a system which we’re so lucky with in the UK here, where we can continue to learn.  And that’s not just for learning for the knowledge of people who might encounter the health system in the future.  It’s to learn for those people who’ve joined the National Genomics Research Library, who’ve already trusted us to be the custodians of their data, and to do better in the future.  And that’s what our diagnostic discovery work really aims to do.  And sometimes that’s about new gene discoveries.  So all the time new things are being discovered each year.  And if you look at the DNA code, if you like, boil it down very simply.  99% of it is what we call non-coding DNA, I’ll come back to that, about 1% is the genes, which if you like are sort of the books in the library of the DNA, overall DNA code, that we understand relatively well how they’re read by the body.  The bits in between, it’s a bit of a funny, well-spaced out library this one, that’s the 99%, actually we’ve had very little understanding of most of that code in between.  But we’re beginning, and particularly this year, to gain an understanding of how we might interrogate some of those pieces.  And not all of the answers lie in that non-coding DNA, there’s lots of answers still left in genes that we don’t understand well.    But one of the examples I mentioned earlier, and in fact the thing, the single discovery I guess which I’m most proud of having happened in the National Genomic Research Library is this discovery of this non-coding region called RNU4-2.  Which is a funny, like technical series of letters and numbers, but basically it’s a very small patch of the whole DNA code.  Where this year, scientists discovered actually about 60 patients in the families in the National Genomic Research Library where that was the cause of their child’s developmental disorder.  Actually, that knowledge has really rapidly spread across the world.  So I actually saw on social media at the weekend, from one of the scientists involved in the discovery, that the family support group that’s been set up for what they’re calling ReNu syndrome, which I think is a lovely name in itself, speaks to that word hope that you mentioned, Adam.  There are now 248 members of that group, and that’s how fast that knowledge spreads across the world.  And what we’re doing is thinking how we can support those discoveries more broadly, and non-coding DNA is one of those areas where that growth is, but it’s not the only one where we’re looking to support things.  But it’s so exciting, and I think it gives you a sense of the scale of progress that is left to make.  And I think a really important point is that remains a really important area of our focus, it’s not about moving on and looking just to the future, but we need to keep working for the families who are already part of our programmes.    Adam: That’s incredible, that 248 members in such a short space of time.  And I love the ReNu name for that, I agree, I think that’s a fantastic way of positioning it.  Earlier this year, we heard from Lindsay Pearse, whose son Lars received a diagnosis through that groundbreaking discovery of the genetic change in the RNU4-2, or ReNu gene, which was made possible by whole genome sequencing.  She told us what the diagnosis meant for their family.  Lindsay: This feeling that, like, we’ve been on this deserted island for eight years, and now all of a sudden, you're sort of like looking around through the branches of the trees, and it’s like, wait a minute, there are other people on this island.  And in this case, actually there’s a lot more people on this island.  Yes, it’s very exciting, it’s validating, it gives us a lot of hope and, you know, it has been quite emotional too (laughter).  And also, a bit of an identity shift, because I spoke earlier about how being undiagnosed had become quite a big part of our identity, and so now that’s kind of shifting a little bit, that we have this new diagnosis, and are part of a new community.  Adam: You talked about it there, Rich, I mean, it’s been really seen as a success story for the whole genomics ecosystem, especially the speed at which it all came together.  From the conversations I had with some of the individuals that were involved in the study, from the date of seeing the first findings in the lab meeting to a polished pre-print going live, was exactly 47 days, which in science terms is less than a second.  So that’s how they positioned it to me, incredible.  And you’ve just said there, they set up this support group earlier this year, and already got 248 members, which is incredible.  The impact on families is significant, the mother touched upon it there.  I mean, for many parents there is that relief that it wasn’t something they did during pregnancy, but instead, it is a chance occurrence.  For some, this knowledge means that they can make important decisions, choosing to grow their family, for example.  And it really ends that diagnostic odyssey that many families face, providing answers and potentially ending unnecessary testing that their child is going through.  But I think, and I can talk from personal experience here, that the largest impact is really being able to connect with other families and building that community, you cannot really understate that.  If I look at our own experience of getting a CRELD1 diagnosis for our children, the first time we didn’t feel alone was when we could find that community.  We can support each other, we can learn from each other’s experiences, and really also drive forward further research into that condition through advocacy.  So, I remember seeing that post on the Facebook page, about that RNU4-2 discovery, and this was before I’d even started in the role at Genomics England on the Panel, but you could really feel that excitement and the relief that they had.  And they mentioned that the official paper only had 36 other people worldwide, they found this little Facebook group that they created with five families in, and in the space of, what, 6, 7 months, they’re already at 248.  That’s all people that understand what they’re going through.  And it’s really hard to describe, it’s like finding your family that you’ve never met, people that understand, and they really get what you're going through.  And being able to share tips, advice, learnings, and things that everyone’s going through at different stages in their child’s life.  So, I really don’t think you can talk highly enough of that, that community aspect, and that’s just been amazing to see.  And, look, this new era of research into the role of non-coding RNA genes, it really may open more opportunities for diagnoses for patients, participants potentially leading to hopefully more breakthroughs in the year ahead.  So now we’re going to move on to why it’s so important to engage patients and participants in the genomics world.  So, we’ll now hear a clip from Helen White, who is the Vice-Chair for cancer on the Participant Panel.  Now Helen and I have been working really closely together as Vice-Chairs in this interim leadership role, to really ensure that we continue advancing the Panel’s strategic initiatives while we recruit that new Chair.  So it’s been amazing learning and working with Helen.  In this clip, she discussed an important topic that’s been very much top of mind of the Panel, which is the importance of involving the patients and public in genomics research.  Helen: I think, you know, as patients, members of the public, we’re eager to get on and for change to happen and things to be better, but it’s, yes, a big, big process.  But also, good to hear that you talk about it being a collaborative approach, it’s not just Genomics England, it’s the NHS, it’s members of the public and patient voices, it’s other organisations working in partnership.  Adam: Now I think we all recognise the importance of engaging patients and public to ensure diverse communities understand the benefits of genomics, and actively involving patients and participants in the research, to make sure that they’re including the perspective of what matters most to them.   Rich: I mean, it goes back to the thing that we really see as central to the value that we at Genomics England can provide.  So we increasingly think of ourselves as a data and evidence engine for national scale genomics, and I think a really important to call out there is that evidence is broad.  And part of that evidence is about public expectations, public preferences, and patient preferences.  And if you think about the big things that we do and where we bring that value, and bring that data and evidence engine role, is, you know, firstly in the digital infrastructure that we build and the data that we hold and present to our various users.  Secondly, it’s in the evidence that we distil from that, and very much thinking about part of that being evidence in and around, including that piece on what people expect, this isn't just about hard science and health economics, this is an equally if not more important part of that.  And then thirdly, it is the third area of our focus is on that engagement piece, because that’s so fundamental.  And I think you and Helen called that out absolutely right, about that being, that’s integral to the whole process, and it’s the beginning of any programme you need to start with understanding what the big drivers are, what the expectations are, and doing this very much together.  That’s one of the reasons we’re so fortunate to have the Participant Panel we do, in our Newborns Programme the Panel have been an important part of that design from the outset.  It’s also about broader engagement with different communities, people who currently don’t engage with genomics, because they’ve had no need to, sort of understanding that piece.  And I think we’ve definitely seen over time in health data research, but also research more broadly, where it’s quite easy for these things to be disconnected.  And that results in two things.  It results in research happening about interesting esoteric stuff, but not on the stuff that makes a difference for families.  And I think that’s really important, because researchers need to be directed in the resource limited world towards the things that really make a difference.  So that’s the first thing.  And the second thing is, it’s very easy, with the best will in the world, for people to make wrong judgements about what people are or aren’t content with, and you need therefore to be absolutely transparent about what the research is.  Be really clear about what those questions are, and let people challenge you, right from the outset, so that we can design research studies, but also, the system as a whole, together in a way that everyone has a say.  Not everyone has the same view, but how we can develop a system that takes into account those things and gets that balance right.  This is about making a difference to people’s health outcomes, thinking about how we achieve that, while also balancing off all of the different views there are, is really important.  And that’s at the heart of it.  And it can be scary, because it’s right that there is that challenge out there.  And it’s one of the things that I think we’ve learnt at Genomics England, how important it is to be really open to that challenge, and to do that piece really early in all of our work, and have it there baked into our governance as well, for example, the Participant Panel.  Adam: Absolutely, and I think you’ve summarised all the key areas there really well, in terms of the importance of that engagement.  And one other area I’d just like to pick up on is the impact it can have on the patients or the participants, simply by having that connection with the researcher, that’s doing all of the amazing stuff that for some of us, it’s really hard to comprehend.  But having that interaction and collaboration with them, it’s so important in terms of, again, I go back to giving you that hope.  And a real highlight for me at the Genomics England Research Summit was when Hannah, one of the members of our Panel, she came running over to us and she was just beaming.  And she said, “Guys, you’ll never guess what, I’ve just met the scientist who discovered my daughter’s diagnosis in the NGRL.”  And you could see that she was so excited, you cannot understate the impacts that can have on them as a family.  Like having that interaction and that personal connection with the person that really in some ways kind of changed their lives, in terms of understanding more about what that could mean for their daughter growing up, and how they’re managing the condition.  So, it’s amazing when you can see those highlights and hopefully we’ll see more of those.  And it’s also really important that we get that diversity I think, as well, in that collaborative approach, just to make sure that it is equitable for all.  And that really brings us on nicely to the next topic, which is about how do we bridge the gap between those diverse communities, and make sure that we’re reaching everyone as best as possible?  So we’re now going to hear a clip from Sandra Igwe.  Sandra is a CEO and founder of the Motherhood Group, speaking about the Generation Study.  Now, Sandra spoke about the importance of building trust, and how it is vital to engage with a diverse group of communities in the design of research studies.  Sandra: 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.  Adam: So, Rich, did you want to talk about why it’s so important to have that diversity?  Rich: Yes, I mean, it’s critical.  One, I mentioned earlier, our vision as an organisation is a world where everyone benefits from genomic healthcare, and that word “everyone” really resonates.  I think Sandra has been really an important part of the work that we’ve done over the last couple of years, particularly through our Diverse Data programme.  But I think one of the real challenges for us is how we make sure that that is something which is embedded across all of our work.  And that’s something that we’re really focused on at the moment, how we embed the learnings that we’ve had through that standalone Diverse Data programme into everything we do.  Because we’re absolutely committed to that, and I think that is engagement with the diversity of different groups relevant to each programme.  I think one of the real important things is that transparency piece about actually that it’s hard to achieve equity in healthcare, full stop, because of historical underinvestment in some of these areas.  And I think being clear with people about that is a really important step, and then talking really practically about why it really makes sense to take different approaches.  And so one thing about our programmes and how we think about the future overall, if genomics is going to make a difference to more than half of healthcare encounters, it needs to be something that across all communities, and across the large majority of people in each of those, that this is something that they want to be part of.  Because it’s going to make a difference for them or their families or something they really buy into.  And that’s why this isn't just about thinking only about specific programmes where this is a question, it’s about making sure that we’re designing a system, developing the evidence that is really broadly applicable, and continues to learn.  Because we know that what we learn today is hopefully an improvement on where we are, but we continue to learn and learn and learn.  And it’s about creating a system that does that, and does that equitably, or as equitably as we can.  Adam: So we’re now going to hear from Moestak Hussein, who works to build and embed cohesion, inclusion, and social justice, in her role at Bristol City Council, in public health and communities.  Moestak talks about the value of co-production, and how this can help to build trust with communities who have historically been underserved or mistreated.  Moestak: If we talk about co-production, true co-production is really creating a power balance where there’s no hierarchy, it’s an empowering model.  It empowers both the researchers or the person that comes in, but also the communities that participate, and you all start on the same level, on the same outcomes and the same goals and aims that you want to achieve.  Adam: So, if I look at that from our perspective on the Panel, I think co-production in genomics research, so using participant data in the NGRL, is certainly what we’d like to see much more of.  To ensure that research is not only relevant to its intended audience, but also aligns with broader democratic principles of citizenship, accountability, and that transparency as well.  But look, we have to be realistic.  Some genomics research projects are not going to lend themselves to meaningful patient and public involvement in the early stages, but it’s really important later on in the research pathway, if the findings identify a patient population who might benefit from that research.  At the moment, involvement of patients and participants, carers in research, is really not great, in terms of the researchers using the NGRL.  So, in conversations what we’re hearing is they’re saying, “Well, we don’t know how to do it, we don’t know what steps we should take.”  Or “We don’t think it’s relevant because we do this particular research.”    But really, our view is that some PPIE, or patient and public involvement engagement is better than none.  Some may not be relevant for all stages of the research pathway, we’re not really seeing enough of that happening at the moment, and some papers are even being published without any context of the participants’ lived experience at all.  Which can actually be quite frustrating, if you're that patient or parent, and you see a paper published, and you think, well, actually, why didn’t they reach out to us?  Just to understand a bit about the symptoms that we’re experiencing, what are the challenges that we’re facing, just to really add that important context.  So, I think there’s certainly an opportunity for us on the Panel, certainly for Genomics England, to be that kind of guiding light for those researchers.  Whether it’s providing them with researchers, research papers, or a hub of patient advocacy organisations that are already connecting those patients with researchers.  It’s all about signposting them the relevant information, so I think there’s certainly things we can do there.  And it really fits in with the bigger engagement piece.  So, whether there’s a landing page or a dedicated website that shows them, where do they go, what are the steps that they can take, what’s the best practice, what’s worked well for another researcher, and how did that lead to really great outcomes for the families involved?  That’s where I think we can all play a part in guiding them on that journey, rather than it just being a case of, they’re not doing that patient and participant engagement very well, and kind of criticising it.  Let’s reach out to them and say, “Look, we can help you and guide you on that journey.”  Rich: I really agree with the need to make those connections happen.  One of the things I think that is often missing is just a confidence just to crack on and do some of this stuff.  And I think, actually, looking at the ReNu syndrome experience, that was work that was swiftly done.  Scientific at the beginning, the initial publication put out there so that people could understand, and was quite medical by necessity, in terms of the speed of getting information out there.  And then very quickly, and quite organically, patient support groups have formed, and also, the scientists are working with that group.  I had a really interesting conversation with Sarah Wynn, who’s the CEO of the Unique last week, about how some of that has played out, how the role they’ve played in facilitating some of that.  And some of it just comes down to sort of really simple things, and working through how you can set up Zoom or whatever meeting, for people to learn about the condition.  And how you preserve anonymity, where that’s appropriate, but also allow people to have discussions about their loved ones where they want to, etc.  So it’s partly just about giving people the space and the confidence to get on with some of these things.  And as you say our, one of the things we at Genomics England are quite thoughtful about, and I think it’s a really good topic to continue talking to the Panel about, is how we get that balance right.  Where, actually, us being a connector and, as you say, signposting useful resources or ways of doing these things, just to break down some of those barriers.  Because almost always the research groups, when they discover something new, this is really new territory for them, and they’re often nervous about doing the wrong thing.  And so it’s about breaking down some of that anxiety actually I think.  Adam: Yes, absolutely.  In our case, with our condition that we’re advocating for our son, we’ve been working with a researcher.  And it’s almost on us as well just to kind of share our story with them, and making them feel more comfortable to ask us questions and be very open and transparent about the more we can share, the more that can hopefully benefit their research moving forward.  It’s very much a two-way thing as well, but I like what you said there about having the confidence just to kind of reach out and start those conversations, and have that starting point.  Next topic, we’re going to look at some of the innovations that are on the horizon, that we’re seeing in the world of genomics.  So, Rich, do you want to take us through what are the most exciting things that you're exploring at the moment?  I know we hear a lot about AI and the technological aspect, so why don’t you take us through some of those?  Rich: Yes, so I guess this comes back to that question where we’ve been looking forward, you know, where might genomics be impactful and making a real difference to people’s lives, to helping us have a more efficient healthcare system in the future?  And I think part of that is about this general shift.  You know, genomics technology, we just take for granted now how much it’s shifted, how it’s within the means of the healthcare system to generate genomic data.  And we’re really fortunate in this country because of the digital infrastructure that we’ve been able to build together with the NHS, that opens up a lot of these questions.  And it’s just extraordinary the time we’re at in genomics, so almost take those two things for granted, which we should never do.  The change in genomic testing technology, which continues to advance, and secondly, thinking about the digital infrastructure, like the nuts and bolts of what we’ve got, and the ability to safely store and reuse and analyse some of that data at scale.  And point at two big things.  Firstly, genomics enabled therapies are changing a lot.  So, our understanding, our ability to make a diagnosis, or understand what’s different about a cancer, for example, mean that in various ways it’s becoming feasible to do more tailored therapies.  Where knowing that, the genomics nitty-gritty of that condition, helps you tailor that, or create sometimes even a bespoke personalised, truly for that one individual, therapy.  And in rare conditions we see that with the so-called N=1 therapies, but also with gene therapies and so forth.  And in cancer we see that with the cancer vaccines, for example.  So that’s an enormous area of change, and one of our responsibilities is to support that sort of research, to help identify people who might be eligible for trials or treatments.  But it’s also to work with the ecosystem to think about how we can help support the generation of evidence that means that those therapies can be affordable and so forth, on a scalable basis.  So that’s one really big area of excitement.  And we see our Rare Therapies Launch Pad being part of that, the National Cancer Vaccine Launch Pad, being part of that.  So that’s thing one.  Thing two is AI and machine learning, and I think sat on alongside the sort of broader picture of saying, there’s a lot left to learn, there’s enormous potential in genomics in terms of playing a role in many different situations, not just in rare conditions, in cancer.  And we know doing that well, but also scaling it, making it really efficient, so that we can do that in a context of a really busy health service, one of the answers is making sure that we’re leveraging everything we can about the potential of AI.  And there’s lots of different ways in which that can be supportive, I won't list lots of them.  But one of the things that we’re doing at Genomics England and working with the NHS is thinking about the most promising areas.  And some of those are quite, like, down and dirty, if you like, so sort of saying, which jobs are there that we can use AI, if you like, as a co-pilot, alongside experienced scientists, to speed up their work?  And we’re really excited about the role we can play in a few ways actually.  So the first one, back to that sort of data and evidence engine point, is helping organisations who have a tool, help validate it for use in the NHS, and say, “Does it perform to this standard?  What do we want to say about how it performs from an equity point of view?  And from a clinical safety point of view?” etc.  And making that leap from stuff that makes a Nature paper to stuff that lands in clinic is surprisingly challenging, and that’s one of our roles.  And we really enjoyed working with various companies and academics over the last few years on that.  We did some work recently with Google DeepMind, on their AlphaMissense tool, thinking about how we can think about that role that might play, for example, in speeding up the interpretation of rare variants that might cause rare conditions.  And there’s enormous potential in all sorts of different parts of the sort of end to end of genomics playing a role in healthcare.  And then I’d also say one of the really important things is because genomics in many ways just needs to be part of healthcare and not be treated differently, we also need to recognise where there are questions we need to work through really thoroughly that are a bit more bespoke.  And one of the things that we’re really committed to doing, as we look to the future, is making sure that we can support on some of those questions that we really need to be clear on.  I’ll go back to that point on, what do we mean about making sure we understand how a tool is working, and whether it’s producing results in an equitable way for all different communities?  How do we understand that?  How do we explain what we understand about the performance of a tool?  How do we make sure that patient identifiable data remains non-identifiable if a tool’s been built, trained on data?  Working through some of those questions.  But they’re really important for us to do, and we’re enormously excited about the potential, and we’re really committed to working through in detail how we can make that path to adoption safely and in the way that everyone would expect and desire as rapid as possible.  We’re just one step in that process.  But we really see a sort of important role for helping people who are producing various tools or various use cases, helping them prove them, helping them validate them, and making the system more efficient overall, but in ways that we really understand.  Adam: That’s fantastic.  Look, not that I'm biased at all, but I can tell you that the AlphaMissense innovations that are being developed are shared a lot internally at Google, it has been seen as an amazing success case.  So hopefully we’ll see more on that moving forward.  But in the next clip, we’re going to hear from Francisco.  So Francisco is the Director of Bioinformatics at Genomics England, who tells us more about the application of AI and its benefits in genomics in healthcare.  Francisco: So AI is already driving the development of personalised medicine for both research and healthcare purposes.  Now at Genomics England we are investigating the use of AI to support a number of tasks, for the potential impact in both research and healthcare.  In the context of healthcare, we are talking about AI tools that can support the prioritisation, the ranking of genomic variants to allow clinicians to make more accurate and faster diagnosis.  Adam: While all of these innovations sound really exciting, it’s really important that we just continue to bring that patient and participant community on that journey, just to ensure that they really understand the full benefits, and we talked about that on the episode today.  I know that the panel has always encouraged Genomics England team to look at its boots while shooting for the moon.  I really like that phrase, just to make sure, look, we can’t forget where we’ve come from to make sure we’re taking people on that journey.  So, we’re going to wrap up there.  Thank you to Rich Scott for joining me today, as we reflected on key milestones for 2024, and looked at the year ahead for both Genomics England and the wider genomic ecosystem.  If you enjoyed today’s episode, we’d love your support.  Please like, share and rate us on wherever you listen to your podcasts.  I’ve been your host, Adam Clatworthy, this podcast was edited by Bill Griffin at Ventoux Digital and produced by Naimah Callachand.  Thank you everyone for listening. 

In this explainer episode, we’ve asked Katrina Stone, Clinical Genetics Doctor, and Clinical Fellow at Genomics England, to explain what happens when you go for whole genome sequencing for a rare condition. 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 when I go for whole genome sequencing? I'm joined by Katrina Stone, Clinical Genetics Doctor, to find out more. So, Katrina, first things first. What is the purpose of whole genome sequencing?   Katrina: The purpose of whole genome sequencing is to try to make a precise genetic diagnosis for someone with a suspected or confirmed genetic condition.  Florence: And why might someone get whole genome sequencing?   Katrina: They might get whole genome sequencing because they are known to have a condition which is likely to be genetic, but the medical team wants to find out what the exact genetic cause is. In other cases, the diagnosis might not be known, and the reason for doing whole genome sequencing is to find out whether there is a genetic condition present.  Some of the benefits of having the test is that. If a condition is identified, this can provide an explanation for the family about what's been going on, and it can also bring to an end further unnecessary investigations. Also, if a genetic diagnosis is confirmed, this can sometimes point towards other things which might need to be kept an eye on for the individual.  In addition, once a diagnosis is confirmed, a doctor can advise the family on the likelihood of other members of the family or future children being affected with the same condition, and they can use this information to help with future family planning.  Florence: So, then what happens when a person physically goes to get the test?   Katrina: In most cases, an individual will see a specialist doctor. This might be a genetics doctor, but it could be a doctor specialising in another body system. They'll do a full assessment of the individual, including finding out lots of information about them and their family, and also examining them to look for any clues that might point towards a specific genetic diagnosis.  Once the family have decided to go ahead with the test, their consent will be taken, where the test will be explained in more detail, including the pros and cons of going ahead with the test and after that samples can be taken. Usually this is a blood sample, but occasionally a saliva sample or cheek swab could be taken.  The best way to perform whole genome sequencing is with a sample from the person being tested along with both of their parents. And the reason for this is that it makes it easier to separate out genetic changes that are more likely to be significant from those that just represent harmless genetic variation what makes us all unique.  Florence: What happens to this sample after the test has taken place?   Katrina: So, the blood samples will go to a genetics lab where the genetic material known as DNA is extracted. The DNA is then sequenced, so we get an electronic file of all their genetic information. This is then analysed firstly by a computer which picks out changes or variants in their DNA, which are more likely to be significant.  After this, a trained clinical scientist analyses the data in detail. Sometimes there isn't a clear-cut result, and the scientists might need help from others and interpreting the result, but if there is, they can create a report which details the likely diagnosis.  Florence: And finally, how will the patient get the result from their whole genome sequencing test?  Katrina: Usually, the result is fed back to the patient and their family by the clinician who arranged their testing or one of their close colleagues. It's important to note that not everyone will get a genetic diagnosis from the test. This doesn't necessarily mean there isn't a genetic diagnosis present.  There are several reasons why tests might be negative. One is that no test is perfect and something important might have been missed because of the way the test works. Or it may be that the person being tested has a change in a gene that hasn't been described as causing a disease before, so we wouldn't even know to look for it.  There's also a possibility that there isn't a single genetic cause for their symptoms. Rather, lots of minor genetic factors are causing their condition. We're not very good at testing for these yet. Finally, there could be a non-genetic cause that just hasn't been identified yet.  One of the benefits of having a whole genome sequencing test is that the data can be stored and looked at again in the future, either in light of new evidence or once our knowledge of genetics has improved.  Florence: That was Katrina Stone explaining what happens when you get whole genome sequencing. 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 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.