The Festival of Genomics and Biodata is just around the corner, and we’ve had the opportunity to sit down with some of our expert speakers to get a sneak peek into what they’ll be discussing, and why they think you should come along to the event.
In today’s interview, we speak to Morghan Lucas (Co-Lead, R&D, Medical Genetics Center, Munich) about emerging omics, cancer diagnostics, education and her experience at the Festival of Genomics and Biodata.
Register for the Festival of Genomics and Biodata here.
Please note transcript has been edited for brevity and clarity.
FLG: Hi everybody. Today, we’re joined by Morghan Lucas from the Medical Genetics Center in Munich. Morghan will be joining us in January to speak at The Festival of Genomics and Biodata, and we’re very lucky to get some time with her this morning for a quick chat. So, Morgan, over to you, could you tell the audience a little bit about yourself and your career?
Morghan: I began my research career in Australia, studying neuroscience and later shifting to cancer research. During this time, I developed a really strong interest in technologies, which led me to pursue a PhD in the field. I completed my PhD at the Centre for Genomic Regulation in Barcelona, under the guidance of Dr Eva Novoa, where I focused on developing nanopore sequencing methods to detect RNA modifications and sequence short RNAs. After my PhD, I moved to Munich, where I am now, to take on a role as the co-lead of research and development at the Medical Genetics Center, or MGZ, which is a diagnostic laboratory. Here, I work with my colleagues to develop new diagnostic methods for a variety of different disorders, with a particular emphasis on sequencing technologies.
FLG: Your career has taken you quite far then, across the world, it’s really exciting. And at The Festival, you’re going to be speaking about your work using emerging omics. Can you tell us about what technologies you’re using in your work at the moment and how they complement each other?
Morghan: At MGZ, our primary focus has traditionally been on genomics, which is the cornerstone of the diagnostics field, I would say. But we’ve expanded to other areas like epigenomics and transcriptomics, and we’ve been doing this with platforms like next generation sequencing and long read sequencing, such as with Oxford Nanopore Technology and PacBio sequencing, as well as other approaches like optical genome mapping. Typically, we combine these approaches to look at different aspects of the genome, epigenome and transcriptome. But looking ahead, I think we’ll also start to explore even more detailed layers, such as proteomics and epi-transcriptomics; epi-transcriptomics is like the epigenome for RNA. I think a key part of our approach is also maximizing the amount of information that we can gather from a single assay. For example, in diagnosing muscular dystrophies, we look at both genetic parameters – like SNVs, SVs, indels, copy number alterations – alongside the epigenome. Also, for other methods, like our Life-CNA method, which is a liquid biopsy-based approach, we are looking at a range of different things from our next generation sequencing data from the genome and epigenome, and incorporating other omics like fragmentomics, which has been very informative for cancer diagnostics so far.
FLG: You mentioned there the Life-CNA method that you’ve developed, which I think, if I remember correctly, has shown positive results in colorectal cancer diagnostics. Can you explain the key innovations of that method, and how it improves upon existing detection techniques?
Morghan: That’s a good question. This method offers major improvements for colorectal cancer so far, for diagnostics, because it’s using an untargeted approach to analyse and sequence circulating tumor DNA, or ctDNA. Unlike traditional methods that focus on specific hot spot variants, this method integrates multiple analysis techniques, things like global and regional DNA fragmentation patterns, chromatin signatures, copy number alterations, a whole bunch of different things. This allows us to detect a wider range of cancer related changes. This makes it more sensitive, but also more applicable to a broader patient application, because we haven’t pre-selected what we’re looking for, we’re doing it in an untargeted manner.
FLG: And when it comes to expanding that method to other tumour types, like prostate cancer and breast cancer, what challenges have you faced when adapting the method? And how did you, or do you plan to, overcome those challenges?
Morghan: This is a great question, because we are in the process of adapting it to so many different cancer types. Like you mentioned, breast cancer and prostate cancer, also pancreatic cancer and for things like Lynch syndrome surveillance or early detection. And all of these things are very, very different molecularly, right? Even in the same cancer type, the difference between patients is great. So, it has been really challenging to adapt to different tumour entities because of the unique genetic and epigenetic signature of each tumor. Our original pipeline, which was developed for colorectal cancer, had many different metrics, and we’ve been trying to refine the pipeline to make it more specific for different tumour entities. So, looking at different signatures that are more specific for colorectal cancer versus breast cancer, and also incorporating new metrics. For example, we have looked at regional fragmentation, but now we want to include more information, for example, like what is the motif at the ends of the fragments? Or ‘end-omics’, you might call it. We’re adding new features, making it more robust and refined, and then hopefully this can tailor the analysis to the cancer type.
Another major challenge with this is more logistical. To make it a more clinically validated method there is the recruitment, sequencing and analysis of a large number of patient samples, from different tumour types, stages and also age-matched healthy controls. We’re currently in the midst of this, and we’re always happy to hear from researchers and collaborators that would like to work with us, and we have many projects going on at the moment.
FLG: It sounds like it could be a really useful tool. You’ve kind of touched on it there, that obviously the most important thing when it comes to tools like this is that they can help patients. How do you envision the method being implemented in a clinical setting, and what are the next steps on that journey?
Morghan: The next steps for clinical validation would be large scale studies across different patient populations to ensure that the method is accurate and reliable, and that we have really robust cutoffs for different parameters of what is and is not cancer. We need to recruit a significant number of patients for this within stages and molecular profiles, and then really work on fine-tuning our models. Additionally, working closely with clinical partners is a key aspect of this, making sure that we can integrate it into standard care workflows. This involves explaining how the method works, and having the first line of care, which is the doctors, be aware of this method and how it works, and what its ability is, and then actually recommending patients have this test. It’s definitely a whole workflow to have it implemented, and having a really robust workflow, analysis, pipeline, all of these things.
FLG: You mentioned making sure that the frontline doctors are aware of it. So, I imagine then there’s quite a large aspect to this that’s educational, in translating these findings to the clinic. That must be quite difficult, I would imagine?
Morghan: It’s difficult, but I also think it’s really rewarding. Research is a big part of our work, and our responsibility is communicating our results – not just to inform people about them, but also to get feedback, right? So, I’m not a clinician, I don’t work directly with patients, but if I talk about this method, and then I get feedback from the doctors about how this is maybe not useful, or it is useful for patients, this is incredibly useful information. It can be difficult and challenging, and there are always lots of different groups of people that you need to communicate with when creating a clinically validated workflow like this. But I also think it’s one of the most rewarding parts of the work.
FLG: It really highlights that need for teamwork and collaboration. Can you discuss the advantages of using a multi-omics approach for enhancing diagnostic accuracy?
Morghan: Yes, I love to talk about this. It definitely boosts diagnostic accuracy because it gives us a more complete picture of the disease at different biological levels. So, genomics, epigenomics, transcriptomics, proteomics, really going from DNA to RNA to protein level, and all of the levels on top of each of those factors, right? And this is especially important since every disease, and even individual cases of the same cancer, really varies from one patient to another, and one disease to another. By looking at multiple layers of information, we can pick up on a wider range of biomarkers, including those that might have been missed if we were using a single omics approach. For some diseases, for example, one muscular dystrophy that we work on, it’s a very complex genetic and epigenetic disease, and we need to be able to look at multiple things, because it requires multiple mechanisms for the disease to manifest. So, we do need to look at multi-omics approaches, not just to improve, but even to do the diagnostics. And I think it’s not just limited to improving diagnostics, but it also helps us understand what’s actually driving the disease, and that deeper understanding can help us develop treatments or targeted treatments, and manage the disease more effectively. Overall, more holistically, I think by taking this multi omics approach we can provide a more personalised approach to patient care.
FLG: It sounds like it’s the way forward in healthcare. Something that you mentioned there was your work on muscular dystrophy, and the epigenetic and genetic factors that are involved. Your work involves using nanopore long read sequencing to study that: what unique insights does that technology provide, compared to more traditional sequencing methods?
Morghan: As you mentioned, we have a study on muscular dystrophy. This particular disease is called facioscapulohumeral muscular dystrophy. It’s quite a mouthful, it’s called FSHD for short. We are in the process of developing an nanopore-based method for diagnosis. This disease is very complex, because it involves methylation changes. It also involves repeat contractions on something called the D4Z4 repeat array, which is a repetitive region of the genome. And there’s also a whole range of genetic and epigenetic parameters that can change. For example, we look at SNVs, SVs, changes in the repeat contraction and the methylation profile. And not just global methylation, but the actual profile of methylation, if it’s increasing over time and over the locus, and also if it changes over the patient’s life.
So, traditional techniques – we use things like Southern blotting, Sanger sequencing and next generation sequencing to do diagnostics for this disease – they can only partially capture some of the aspects of the disease. We have to put usually three or four different methods together to get an understanding of the disease and the diagnosis. Whereas, in contrast, with nanopore we can actually look at all of these things in one assay. We can look at all of these genetic and epigenetic parameters with one sequencing run. We reduce the number of tests, but it’s also more informative because we’re able to sequence long stretches of repetitive DNA without fragmentation, so things like phasing and haplotyping is much easier, or even made possible, by nanopore sequencing. It’s overall more informative. And I think it’s not just informative for diagnostics, but I think it will be informative for prognostics for this disease.
FLG: It sounds like it’s really an improvement on what we’ve had before. Going from having to do three or four assays to just having to do one, I can imagine that there must be a financial incentive there, and also the time incentive, as well. It really is amazing to see technology developing like that, and the things that can be done with it. Given those rapid advancements in sequencing technologies, where do you think the biggest opportunities for innovation in molecular diagnostics will be in the next few years?
Morghan: Oh, great question. I think there’s a few different areas where we will see innovation. One, which has been what we’ve been talking about, is interoperating multi-omics. Looking at all the different facets of disease – protein, RNA and at the genome level – to give us a more comprehensive view of the disease, this can potentially lead to earlier and more accurate diagnoses, and also personalized treatment options. Then another innovation is these real time sequencing technologies like nanopore sequencing. I think this will really revolutionize point-of care diagnostics, because you can do this on site in a decentralized manner, and you can do it very, very rapidly. I think this is going to be a game changer for managing conditions like cancer, infectious disease, response to treatment, and especially in places like the NICU and PICU, where rapid diagnostics is vital. And I’ve started to see this in the last year or two, that these platforms are becoming available. This is really great.
I think another big area of innovation is, of course, AI and machine learning. That’s going to be a big topic at the Festival of Genomics. This allows us to analyse really complex sequencing data and help us discover new biomarkers that are hidden in our data that we didn’t see before, help us predict patient outcomes and develop tailored therapies. So, I think having this really rich information from multi-omics pairs very well with AI and machine learning, because we can really make diagnostics faster, more precise and more personalised. Then with these real time sequencing techniques, we’re able to do it fast, which for some applications is really important. Lots of things are on the horizon, and I think it’s really, really exciting.
FLG: It sounds really exciting! And AI in particular, I think it’s very easy outside of the scientific world to think that AI is just ChatGPT and things like that, but it’s amazing hearing about how these techniques are being used to provide real benefit for patients, and how relevant it will become in our lives. It’s really exciting. And as you say, plenty of talks on that at The Festival of Genomics! I’m sure we’re all excited to hear what’s going on there. It’s interesting to think about what healthcare could look like.
And you’ve touched on this throughout the interview. Your research spans multiple disciplines, everything from epigenetics to transcriptomics. How do you approach collaboration across those fields? And how important is interdisciplinary work to the success of your projects?
Morghan: Oh, I think it’s absolutely important. It’s really been a driving factor in all of my research, being able to bring together diverse perspectives and expertise. It makes tackling these really complex biological questions much more feasible, and I would say fun. Actually, it’s great to be able to work with other people and think outside the box and learn from others. I actively try and connect with experts in various fields, because I don’t know everything, and I don’t want to know everything. I think it’s great to be able to work with others that are experts in their field, and have a real diversity in the approach that we take for problem solving. And I think it’s also really important that people see from these collaborative projects how their research fits into the bigger picture, and how it all comes together. I really believe that a cross disciplinary approach is key to success in research and in diagnostics. Being able to combine different types of data and analysis techniques and ideas, it really can drive innovation, with some of the more exciting breakthroughs coming from the intersection of different ideas.
When we think about collaborations, we think about different areas of research, but I think the collaboration also needs to be not just with researchers, but with the community, with the patients, with the doctors. There needs to be a back and forth between all people involved – the people that have the disease, or the family members of those that have a certain disease, and the doctors that are treating them – about how we can make diagnostic tests or prognostic tests and relevant and useful.
FLG: Do you have any advice for young researchers about how to go around building those networks and those relationships? Because they sound so important to all of this work.
Morghan: Yeah, it definitely takes some time to build up confidence. I think it’s just at conferences, going up and speaking to people. I know it’s very, very daunting to do that, but I have to say, I’ve rarely had an experience where that didn’t work out. I think researchers are happy to talk to people at all different levels. When you’re starting a new career, you have imposter syndrome, and it’s always so difficult to do this, but I think you just have to put yourself out there and talk to people at conferences. And write emails if you’re not at conferences, not everyone has the opportunity to do that. Just engage with people as much as you can and show that you’re interested, and also put forward your own ideas. Trying to have an exchange like that, it just takes time to build up that confidence and get used to it. But it’s really rewarding when you get to that point. And I have to say, it took me years to get to this point of being comfortable to just cold email someone and say, ‘Hey, I really liked your paper. Can we do something together?’ And if they say no, what’s the worst that can come from that? That’s my advice, just to try it, and the more you do it, the less scary it is.
FLG: I think that’s really good advice. It’s always important to remember that the people on the other end of that email have once been in the same position as you have.
Could you tell us what you think the future of liquid biopsies and multi-omics will look like? What might we have to overcome in order to move that field forward?
Morghan: I see a very promising future for liquid biopsy and multi-omics. They could become standard tools for early disease detection. And I think combining them is really the way to go, so we get this comprehensive snapshot of health and disease.
To move forward. there are a number of challenges. One challenge is to have a standardised and validated workflow, it also needs to be a method that is able to work in different labs across the world. So, it needs to be something that’s robust and reliable, and this is always a challenge. Then also managing the massive amount of data that’s generated with these approaches, because we’re analysing so many different things in one assay, it’s very complex to integrate the data to use it in clinical practice. And we touched on education, but also teaching the people that are communicating these results to patients, or using these results to make decisions about treatment or patient care, how it all fits together. So again, it really requires a lot of collaboration across disciplines, about how to use this information effectively for patient care. They are big hurdles, definitely, but also the impact that these approaches can have is really huge and very exciting.
FLG: It all does sound really exciting, and it really sounds like you have done, and are continuing to do, some really, really interesting and important work. But reflecting on your career so far, what’s been the most rewarding aspect of that work, and is there a particular project or achievement that stands out to you?
Morghan: I think just the general knowledge that the work I’m doing with my colleagues is having an impact on patient care. Seeing the application of your work is always something very rewarding. Knowing that you can improve something and that it benefits people, this is really a fulfilling thing.
A project that really stands out to me, it’s a project – or multiple projects – where I was developing tools to detect RNA modifications and to sequence short RNAs using nanopore sequencing. I was doing that during my PhD, and I developed a method to sequence native tRNAs called Nano-tRNAseq, which is used to quantify their abundance and the modification profiles. This started back in 2018 when Nanopore released their direct RNA sequencing platform. So, it was in the really early stages of the technology, and it was not great. It needed a lot of improvement. It was not a robust method at that time. After a few years of working with that technology, it approved a lot, and getting this method to work, that was really incredible. Now, seeing it used in papers where people are finding new insights into tRNA dynamics or adapting it for things like studying tRNA isolation, this is really great. It’s also licensed by a company who’s making it into a kit. I am really happy to see this becoming accessible to the community. My colleagues in Barcelona are now turning it into a diagnostic tool, starting with cancer. tRNAs, they hold a wealth of information. They have transcriptomic, and really rich epi-transcriptomic, signatures. So, that project was rewarding, because it started from developing a method in the early days, and then seeing it go through a lot of iterations, and then becoming something that might be useful one day. And I think that’s all we can hope for in research, is that somehow our research is useful. I would say that was maybe my standout project.
FLG: It must be really exciting, seeing something in its infancy, and then the way it evolves and eventually its real world impact. I think that must be so rewarding and such a nice thing to see. It makes all the challenges that you face at the start worth it.
Morghan: Definitely, yes.
FLG: A final question for you. You attended The Festival of Genomics and Biodata last year, and you’re going to speak this year. Can you tell us what you enjoyed about The Festival and why you’ve chosen to speak this year?
Morghan: I really, really enjoyed The Festival last year. It was the first time I’ve ever been, and I have to say it was the most diverse mix of attendees that I’ve ever seen. There were researchers, clinicians, industry professionals, patients. There really was everything. This created such a unique environment for exchanging ideas, learning from each other, and understanding what the direction of genomics, AI in genomics and patient care, is. I think it gave a really good overview of where we’re at and where we’re going. So, in that way, it was really an enriching experience, and I am really looking forward to coming back next year, because I think it’s really important to share the work that we’ve been doing to a broader audience. Not just the people working in diagnostics, but a really broad audience of people, and get those conversations going about our methods and tools and the direction of research. The Festival of Genomics is a great platform for that. For attendees, I think the biggest benefit of this is just being able to engage with others that are really passionate about these topics, that have a wide range of expertise, a wide range of experience. So, I’m really looking forward to attending next year for those reasons.
FLG: Well, we’re really excited to have you at the event, and we’re really looking forward to hearing your talk. Thank you so much for taking the time to speak to us today. We’re really excited to hear more from you in January.
Morghan: Great. Thank you. It’s been a pleasure.
Register for the Festival of Genomics and Biodata here.
