In this episode of The Cancer Researcher Podcast we interview Professor Charlie Swanton, Deputy Clinical Director of the Francis Crick Institute and Chief Clinician at Cancer Research UK on his research interests, the evolution of the field and how he turned round his failing PhD. Charlie also shares with us what he’s looking forward to at the EACR Congress ahead of his Keynote Lecture and gives some excellent advice to early-career researchers on how to break away from the shyness that could hold some back from asking questions and networking at conferences.
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Our host is Alexandra Boitor, EACR Scientific Officer.
Episode transcript
Alexandra: It truly is an honour to have you here today. You are one of the most prolific and respected researchers in the space of oncology and medicine, and one of the leading examples of building up on discoveries from fundamental research, but also of building up an impressive career. And on that note, you somewhat recently published a paper in Nature about your personal experience with your PhD about making the best out of your circumstances. I think you’ve titled it ‘Turning a Failing PhD Around’. So could you please share with us that story of what you went through with your PhD?
Charlie: Okay, so I did my PhD in the mid 1990s of what was called the Imperial Cancer Research Fund in Lincolnston Fields. This was an extraordinary place. It was a sort of melting pot of scientific discovery and had been the place of birth of many very important discoveries in fields like cell cycle, discovery of oncogenes, understanding of cellular apoptosis, and cellular signaling.
And it was an incredibly vibrant place. We had a phenomenal seminar program. Doors were wide open. You could go in and out of people’s offices, very senior scientists, and ask some questions about your research, and people were only too happy to help. It was an extraordinary environment to work in.
So I started as a PhD student there in 1994 and I wanted to study the cell cycle. One of the original questions I started to ask was why were there three different cyclin Ds. There’s cyclin D1, D2 and D3 and two different kinases, CDK4 and CDK6. And it was a reasonable assumption back then, that the reason there were three different cyclins binding the same CDK was that the cyclins conferred substrate specificity to the kinase. Which they do, but the idea was that perhaps different cyclins could bind different substrates.
And so I set about making these so called chimeras between cyclin D1 and D3, and splitting their domains up and fusing them. So I had sort of cyclin D1-D3 chimeras and cyclin D3-D1 chimeras etc. And, I had to show they bound the kinase, and then that they perhaps influenced the phosphorylation of substrates differently.
But unfortunately, after about 18 months, I realised they didn’t. And I even struggled to get positive controls working. And I was banging my head against a brick wall, essentially, not really getting very far. But what I did know was this scientific environment that I worked in, where I could walk into anybody’s office, and ask them questions about the science, about the experimentation and the systems I was working in, and seek their advice.
And you know, these are world class scientists who had discovered many components of the cell cycle. And it was just such a privilege to be able to walk into their office and talk to them about the challenges I was facing, and they would give me time. I just thought this is just an amazing way of running one’s working life. This didn’t feel like work. I looked forward to going in on a Monday morning and I was essentially paid to pursue curiosity-driven research. What an enormous privilege. And it seemed like, frankly, a bit of a minor problem, the fact that my PhD wasn’t really working. I knew I was enjoying it.
Anyway, the crunch time came and I had to sort of face facts that I hadn’t really got very far. And I hadn’t even got chapter one by month 18 of my PhD. In fact, I hadn’t really got a single experiment to work at all. The time came for me to hand in my midterm report and I didn’t really have any data so I was sort of delaying.
Anyway, the graduate tutor at the time came into my lab and said, where’s my midterm report? And I said, well, I haven’t written it yet because I haven’t got any data and I’m waiting for an experiment to work. And he understandably got quite cross with me and insisted that my midterm report had to be on his desk on Monday morning, otherwise there would be consequences.
So I went back to write it up and handed in what was frankly a pretty appalling midterm report, and that resulted in a fairly urgent thesis committee review where they said to me, well, Charlie, you’ve got two options: one, you go back to medical school and complete your medical training and give up on a PhD, or you can change PhD projects. I said, well, I’m not going back to medical school because I love this too much, I’ll change PhD projects. So they said, well, what do you want to do? I said, well, what I would really like to do is understand why the CDK inhibitors or how the CDK inhibitors, P21 and P27, bind the kinase and the cyclin. And they said, how are you going to do that? I said, well, I’m not really sure. Came up with a few ideas, tested them, and they didn’t work. And in the end, I did it the laborious way by mutating every cell surface exposed amino acid, on cyclin D into an alanine until I found one that didn’t bind p 21 and p 27 and the cyclin still bound the kinase.
And from there, everything fitted into place because round about the same time Chang and Moore had cloned The Kaposi’s sarcoma herpes virus that encoded a cyclin that was homologous to cyclin D. And it turned out that that one domain that I found that could interact with P21, P27 had been mutated on the viral cyclin.
And, I did an experiment that showed exactly that. That the viral cyclin had evolved to mutate those cell surface residues so that it could only bind the kinase but not the cell’s cycle inhibitor. And so it was a dominantly active cyclin that could enable the viral genome to be replicated efficiently without the breaks of the human cell cycle system from inhibiting the cyclin CDK complex.
And for me, that was just a lightbulb moment. It was just the most incredible moment, realising that was the case. You’ve seen something that no one on planet Earth had ever seen before, and I thought right then, I want to do this for the rest of my life. This is the job for me. Of course, those moments don’t happen very often in science, but when they do, oh my god, they’re so exciting.
Alexandra: That is indeed inspiring, your perseverance, but also that your research journey started from the sheer curiosity of understanding how p21 interacts with other proteins. And now you are one of the chief investigators on lung cancer in the TracerX project and are involved in clinical trials as well. Fascinating and truly inspiring.
You mentioned having a choice between going back to the medical school or switching gears with your PhD project. And we well know you’re a physician scientist. So naturally, I must ask, what drew you specifically towards cancer research?
Charlie: So when I was at medical school, I got a phone call at the end of my first year from my father who said that he’d lost sensation between his legs, something called saddle anesthesia, which is sort of very indicative of a lower spinal problem, often spinal tumours. And that’s indeed what he ended up having. It turned out the spinal tumour was a high grade B cell lymphoma and he had chemotherapy and radiotherapy over about eight months, very intensive therapy and, you know, 30 years later, he’s alive, fit and well.
And I thought back then, when I got that phone call, we didn’t know what this tumour was. They thought it was a much more aggressive tumour than the one it turned out to be. Or at least they thought it was going to be an incurable tumour. But the biopsy showed otherwise and showed it was a lymphoma that is curable potentially with chemotherapy and now more recently, Rituximab, a monoclonal antibody against CD20.
So I thought back then, you know, this was a terrible year. He was very sick, both due to the tumour, but also due to the therapy. You know, the doctors looking after him and the chemotherapy regimens they were using saved his life. And I thought to myself, well, how did this all come about?
And it’s obvious how it all comes about. It comes about through meticulous discovery research that leads to new cancer drugs, that led to randomised phase 3 trials that either show improvement or not. And each step of improvement incrementally improves survival, modestly, but taken together over decades of research leads to cures and I thought to myself I wanted to be part of that one day.
Cancer was clearly the greatest unmet need when I was at medical school. We’d made great inroads in cardiology. Oncology seemed to me back then to be one of the greatest challenges, and still is. I think that along with neurodegenerative disease are the two sort of biggest challenges that face discovery and clinical researchers now.
I’m very fortunate to have been allowed to work in this field, both as a medic and as a scientist funded by Cancer Research UK over the last best part of 22 or 23 years. It’s been an extraordinary journey seeing the way in which just in those two decades, cancer survival times have improved in several diseases. How our therapeutic regimens have advanced. How immunotherapy’s now the mainstay of the management of many solid tumour diseases. And really also seeing the way in which technologies have advanced that have enabled us to open a window on a world of molecular biology and cancer that’s revealed sort of the inner intricacies of cell division, cell communication.
And most importantly, how the immune system interacts with an evolving tumour. I think it’s simply staggering what we’ve learned in a very short time from advances in the community.
Alexandra: You’ve half answered my next question because I wanted to ask you, what would you say are the major changes you noticed in the cancer research field since you started working in it? And I’m interested in finding out your opinion, both on research topic evolution, which you’ve briefly touched on, but also on how the life of a researcher has changed over the years.
Charlie: Yeah, great question. So I think one of the biggest changes, in the last two decades, is this explosion in data, which is a good thing in many ways, but also presents new challenges. And, I think that should come potentially with a health warning, which I’ll explain in a minute.
But when I first started as a discovery scientist in the mid nineties, bioinformatics didn’t really exist as a specialty. And certainly there wasn’t the sort of level of data that there is now, And to some extent that’s been generated by new technologies such as next generation sequencing, which created this explosion in data, in terms of DNA and RNA sequencing, and more recently, attack, seek and other technologies.
And actually we’ve got more data than we have scientists to analyse it. And along with that, of course, is deep learning, artificial intelligence, machine learning tools, that are further illuminating biology in ways in which we could never have imagined two decades ago. So if you look around an institute like the Francis Crick Institute, where I work, and think to yourself, well, how does it differ now compared to 25 years ago?
Without a doubt, 25 years ago, there would have been many, many more people at the bench than there are today. Many postdocs are sitting in front of a computer processing data now, because there’s so much more data than there was two and a half decades ago. and also, because the technologies have advanced to such an extent, there’s a need to have experts that run these technology course. And so what I’m also seeing is for instance, at my institute, we have over 15 technology platforms. So these are laboratories that run, for instance, like microscopy, cryo EM, flow cytometry, advanced sequencing, etc. And they’re highly specialised technologies that need to be run by people doing this full time.
And so what I’m seeing is that postdocs have a sort of menu of experiments that they’re almost contracted out to these laboratories and postdocs and PhD students act in many ways like conductors conducting broad experimentation to address their question, utilising these different scientific technology platforms. And that certainly wouldn’t have happened at that scale 25 years ago.
So what about research topics? Well, the obvious research topic that I think I’ve mentioned already, to some extent, is this field of cancer immunology. In the mid 90s, funders were abandoning cancer immunology area to develop because they’d largely given up on this idea that the immune system could be used as a tool to fight cancer.
Well, of course we know thanks to Honjo and Jim Allison and many others that that’s clearly not true, that there were very fruitful approaches; we just needed to look harder. And of course, the finding of CTLA-4 and PD-1, these sort of breaks on the immune system, have opened up a whole new field of cancer immunology that have led to cancer vaccines, checkpoint inhibitor therapies, CAR T-cell therapies. The modification of T-cells to target tumours, as well as biological therapies like bispecific antibodies, antibody drug conjugates, and what have you, that essentially use the immune system or components of the immune system to target tumours more effectively. And that’s been incredibly exciting.
In my field, I think, the area that changed the most for us is sort of understanding now that cancers are evolutionary phenomena, that are constantly subject to random variation due to genome instability, chromosome instability, and point mutagenesis, and that provides a substrate upon which natural selection acts and selection in a tumour can manifest in many different ways, drug pressure, hypoxia, radiation therapy, predation from cells around the tumour as the tumour is growing, being starved of resources and what have you.
And this evolutionary force plays out across the disease landscape from diagnosis through to either cure or death. And understanding cancer as a sort of evolutionary phenomenon, I think helping us design trials more effectively. It’s helping us design drugs more effectively. And biomarkers and mechanisms, lead us to detect tumours earlier as well. And I think that’s been the sort of biggest change in my view, the way in which we run our lab is thinking about cancer as an evolutionary and adaptive conglomerate of different cell types.
Alexandra: Switching gears in our conversation, I would like to ask you about your own research. I mean, you have an undeniable talent for bringing different research topics and fields together. Your lab works on cancer evolution and genome instability, covering issues such as tumour heterogeneity, clonal evolution, resistance to therapy. Bringing together functional cell biology with cancer bioinformatics and clinical trials, elements of cancer prevention, as seen in your recent papers looking at the impact of air pollution on lung cancers, diagnostic and treatment. You really do seem to cover the entire spectrum of cancer research through your work. So, what I’m really curious about is, what is your favourite research question or project that you had the opportunity to work on?
Charlie: That’s quite a question! I think, probably, the field that I’m most excited about right now, is this area of molecular cancer prevention. So what do I mean by that? Well, thinking about a future. A little bit like cardiovascular disease, where we can offer a patient a long term treatment like a statin to prevent patients getting cancer.
Why is now the time for that type of approach? I think it’s because really of seminal work from people like Allan Balmain and before him, Isaac Berenblum, who posed this question, how do cancers start? And you know the model of cancer initiation that I was always bonded to was this very simple classical model where carcinogens cause cancer by mutating DNA.
Mutant DNA results in driver mutations, which expand clones into subclones, which result in secondary and third, and fourth oncogenic mutations or tumours suppressor gene mutations that lead to a frank cancer developing. Well, it turns out that Allan Balmain and colleagues have shown that most carcinogens don’t mutate DNA.
So how are they causing cancer in rodent models in that case is the big question. And so Allan and colleagues have been really pioneering forces behind this idea that Isaac Berenblum proposed in 1947, that cancer is a sort of initiation, it is a two step event. And actually it wasn’t just an idea; he underpinned this with very elegant mouse experiment work, where he showed that cancers require two steps, an initiating step and a promoter step.
We now know the initiator step as a result of pre-existing mutations in normal tissue that occur just by consequences of ageing from wonderful work from people like Peter Campbell, Inigo Martincorena, and others at the Sanger showing that we’re essentially a patchwork of mutant clones. James DeGregory, for example, estimates that in a human body of a 60 year old, there are 100 billion cells with a mutated oncogene. That is a phenomenal statistic. And that tells us that cancer at the cellular level is incredibly rare, given that we’re all a patchwork of mutant oncogenic clones.
And so these mutations sit there for the lifetime of the patient and often don’t cause any problems at all. So something else is required and that’s what Isaac Berenblum referred to as a promoter, that we know in some cases can be an inflammatory process. We’ve shown in a context of air pollution for example. Part of that inflammatory process we think is mediated by interleukin-1 beta (IL-1β), with very good evidence from the CANTOS trial that antibodies against interleukin-1 beta can actually prevent lung cancer from initiating.
So we’re super interested now in trying to understand how these carcinogens drive tissue inflammation that contributes to the promotion of these pre-initiated cells that occur in normal tissue with oncogenic mutations, and I think that represents a formidable challenge, but also a very exciting one that could lead to new therapies that can actually prevent these mutant clones from evolving into frank malignant disease.
Alexandra: That sounds so interesting, I can’t wait to find out more. Are you planning on sharing some of the data you have on this project with us in June at the EACR 2025 Congress as part of your Keynote Lecture?
Charlie: Yes, I absolutely am. That’s exactly what I’m going to do.
Alexandra: There are only a few months left now then. So if you’re interested in the latest developments on Professor Charlie Swanton’s research, join us for the EACR Congress in June in Lisbon. Early rate registration deadline is on 28 April 2025. Discover the programme here.
So as I was saying, your Keynote Lecture is most certainly one of my highlights for the Congress to come, especially after the little teaser that you’ve just given us. But to reverse the question, could you share with us one thing that you are looking forward to at the EACR Congress in June?
Charlie: Well, I think what I look forward to most actually is interacting with colleagues, particularly the junior colleagues, who will be at this meeting. I often find the best questions, the most challenging questions, come from those who are newest to the field. And I think the reason for that is because they approach the field in a very unbiased way with no preconceived ideas.
And I think that’s the beauty of science in so many ways. It’s that it’s non hierarchical. A PhD student or a master’s student has as much to contribute to the scientific endeavour as a PI who’s been in the field 30 years. And it’s always those questions at the end of the lecture that stump me, that make me think we need to address this when I get back to the lab when I leave Lisbon and get back to London. And I think it fuels discoveries. It fuels the curiosity that essentially keeps us in this job. We are always challenged by our data, and there are always flaws in it, in all our data. And I think being able to talk to people frankly about our data openly at conferences like the EACR Congress, it’s a real opportunity to get real time feedback from junior and senior colleagues alike and address those experimental flaws when I get back to London over the next year or two, you know, it’s a constantly evolving field and one that we constantly need to be on our toes about to address and provide the highest quality data possible.
Alexandra: And that actually brings me to my last question. So you said you’re looking forward to networking with your colleagues in the field. But whilst this might come natural or relatively natural to more senior scientists, it is often quite challenging for early career researchers. So I was wondering if you’ve got any pieces of advice to encourage them or to help them network and ask questions at conferences in general and at our Congress in particular.
Charlie: Yeah, I think that’s a great question. I think, first of all, don’t be shy. I think there’s always a tendency to not ask a question if you’re in the audience, because you’re worried you might embarrass yourself. I would say, there’s rarely a stupid question in science, and often the questions you think are the most stupid are the questions that scientists either haven’t thought of, or they’ve thought of but can’t answer, and stumble them.
So, I would encourage everybody to speak up, to ask questions if they don’t understand the logic, ask for clarification, and most importantly, at the end of the talks, go up to the speakers and talk to them and introduce yourself and ask them yourself what’s perplexing you or offer up ideas for the next experiment.
I’m always super impressed when junior faculty or PhD, postdocs, master students come up to me at the end of a conference or at a poster or at the bar afterwards and ask me a question. Very often I won’t have a good answer or very often, I won’t even have thought of the question, and that’s as instructive for me as anything, it’s extremely helpful getting feedback from people perhaps new to the field. I’m always very impressed when the juniors have the boldness and bravery to introduce themselves and ask questions and put themselves out there. And that’s what science is all about at the end of the day.
So just don’t be shy and enjoy it and accept the fact that in all likelihood, the scientists you’re talking to, won’t know the answer to your question.
Alexandra: Thank you. I’m sure your advice put some early career researchers’ minds at ease a bit and hopefully encourage them to be more interactive when they go to conferences. Thank you very much for your time Charlie, we really appreciate it. We know you’re really busy and thanks again and looking forward to meeting you in person in June.
Charlie: Lovely to talk to you. Thanks so much.
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