Titans of Science: Charlie Swanton
It’s our final Titans of Science offering of this series, with world-leading cancer expert Charlie Swanton. We’ll hear how the latest developments in our understanding of cancer’s mechanisms are shaping treatments and preventative measures…
In this episode
01:40 - Charlie Swanton: What is cancer?
Charlie Swanton: What is cancer?
Charlie Swanton, Francis Crick Institute
Charlie Swanton was born in Poole in Dorset on the 24th of February 1972. He attended St Paul's School before he continued his studies at University College London and it was there that his interest in oncology, the study of cancer, began. He's a world-leading lung cancer expert and he studies the management of metastatic cancer and also drug resistance and incurable cancers. He's won dozens of prestigious awards for his work. He's currently the Deputy Clinical Director at the Francis Crick Institute in London, and the clinical lead in Cancer Research UK. He gave an extended interview to Chris Smith...
Charlie - Cancer refers to essentially an uncontrolled proliferation in the human body that can breach the normal tissue barriers and in many cases can spread beyond those tissue barriers to other organs through either the blood or the lymph or direct invasion and result in what we call space occupying lesions or metastases in other organs. The reason why patients die of this disease is due to subtle metabolic and immune consequences that prevent the immune system from working effectively or drive abnormalities in the way in which we metabolise products from what we eat or how we digest those products, through to just the consequences of the volume of disease on that underlying organ which could be the liver, the lung, the brain, the kidney etc. that ultimately lead to organ failure.
Chris - So if cells are disobeying the normal genetic instructions and they're just growing where they shouldn't, when they shouldn't, does that mean they can also disobey biochemical rules as well? They can basically make any of the things any other cell in the body can make and just start doing that whenever they want so it's a sort of biochemical disease as much as a physical growth disease.
Charlie - I think that's exactly right yes and indeed there was the effect that you've probably heard of called the Warburg effect and cancer cells in general are much more dependent on glucose metabolism, glycolysis, the biochemical breakdown of glucose. One of the sort of hallmarks of this disease is the uptake of glucose very rigorously by cancer cells and we image that in the clinic using something called FDG PET, which is essentially a radiolabeled glucose tracer that's taken up by cancer cells more than surrounding cells and so that helps us image where the cancer is in a patient's body, that is an example of the sort of biochemical consequences of a cancer cell.
Chris - But certain bits of my body, the healthy bits, are talking to other bits, chemically, they're sending signals through nerves in some cases but through the blood for example with hormones, so do cancers also have recourse to that? Can a cancer influence another organ via hormonal signaling for example?
Charlie - Well that is a great question and it's a question that we are thinking very deeply about actually at Cancer Research UK in our Cancer Grand Challenge scheme which is an international grant programme and here we're doing exactly that which is trying to understand the sort of systems level changes that occur in patients with cancer and we're setting questions to address some of those problems. I'll give you one example which is cancer cachexia which refers to weight loss either of fat or of muscle in patients with cancers like pancreas cancer or cancers of the upper gastrointestinal tract, so gastric cancer for example, esophageal cancer and even lung cancer actually, cachexia is quite common and patients lose weight and it's unclear why or how this happens and we've got increasing insights into this metabolic process and as you say this likely comes about through mediators, potentially hormonal mediators that either are released from the tumour or surrounding tissue in response to the burden of disease that suppresses appetite or makes a patient feel sick or nauseous and ultimately reduces their calorific intake and probably also potentially increases their metabolic rate as it were to degrade muscle and fat to presumably liberate the building blocks that are required for the cancer to grow and divide.
Chris - So the cancer is effectively turning itself into the primary thing and using the body almost parasitically. It's growing off the body?
Charlie - Yeah that's the way I see it in some cases and I think it's quite a scary proposition, it's very important to say right from the outset there's no reason behind any of this, this is purely a reflection of genetic diversity in the evolving cancer mass, that is the number of cells and the differences between them genetically. We call this genome instability that comes about because of the inability of cancer cells to repair their DNA effectively or the fact that they have ways of replicating DNA that's less faithful than normal cells so you get more mutations and it's that genetic diversity between cancer cells that acts as a sort of a substrate upon which so-called natural selection acts and so everything we see in cancers is a reflection of that genetic diversity and natural selection playing out.
Chris - What fraction of the population, if we just pick the human race, what fraction of us are destined to have this happen to us?
Charlie - Well I think in western worlds we'd estimate that somewhere between one in three and one in two of us will suffer from or die from cancer now. We've made great inroads into the management and prevention of cardiovascular events and cardiovascular disease. Our progress in cancer and neurodegenerative disease has been slower. I see cancer as sort of the next big challenge that we're tackling after what I would state is a sort of revolution in our understanding and management of cardiovascular disease and the community is doing an extraordinarily good job but we still have a long way to go to develop new therapies, new means of early detection and most importantly prevention, new ways of preventing cancer.
07:15 - Charlie Swanton: Cancer's Swiss cheese effect
Charlie Swanton: Cancer's Swiss cheese effect
Charlie Swanton, Francis Crick Institute
The government announced this week that they are formally launching bowel cancer screening for people over 50 across the UK. Many countries also have similar sorts of screening programmes. Their rationale for doing this isn’t just that it’s a good idea to detect cancers early; they’re saying it’s becoming more common in this particular age group. So, at a time when we can do more, detect more, treat more, and know more about these diseases and their causes, why are we seeing some cancers encroaching on age ranges where they were historically much rarer?
Charlie – There are several potential reasons for this, and it’s both intriguing and actionable. One explanation could be the changes in Western diets over the past 60 or 70 years, particularly in the post-war era. Some might suggest this is simply a reflection of increased energy intake, while others propose that ultra-processed foods might be contributing. Other potential causes that have been mooted include greater antibiotic use, changes in the microbiome, and even pollution—potentially microplastics and other pollutants ingested as part of our diet. Right now, there is no clear answer to the underlying cause of this increased prevalence. However, I suspect there’s something very specific to diet.
Why do I say that? If we compare South Korea and Japan and look at the incidence of bowel cancer in the under-50s, it’s increasing in South Korea but not in Japan. The populations are ethnically similar but have quite distinct diets. This suggests that something about the Westernised diet, which is slightly more prevalent in South Korea than Japan, might offer clues about why this disease is increasing in younger age groups.
Chris – What do you think those risk factors, including diet, are doing? How do they translate into cancer—whether it’s lung cancer, bowel cancer, or pancreatic cancer?
Charlie – To answer that, we need to identify the clearest proximal epidemiological risk factor, which we don’t know yet. My suspicion is the Western diet. The next question is: why might that be?
One possibility is how the diet alters the microbiome. We know some gut bacteria can cause or induce mutations in the gut’s mucosa, and these mutations are implicated in the earliest steps of tumour initiation. But I think it’s more complicated than that.
Recent work by Alan Balmain and colleagues at UCSF has shown that most carcinogens causing cancer in humans don’t induce mutations in mouse models, meaning they must cause cancer by other mechanisms—possibly through inflammation.
Chris – But cancer is a genetic disease, isn’t it? If I examine a cancer cell, I find it’s riddled with genetic changes by the time the cancer is well developed. At what stage do these genetic changes occur to make the cell misbehave? Are you suggesting there’s a trigger upstream of the mutations?
Charlie – If you’d asked me five years ago how cancer begins, I’d have said we’ve largely solved this: it starts with mutations in certain genes that provide the cell with a proliferative advantage.
But recent studies challenge this model. Deep sequencing of normal tissue—skin, lung, and liver—has revealed cancer-causing mutations throughout our bodies, including in the eyelids.
Chris – Even in young people?
Charlie – Yes, even in young people, although these mutations become more prevalent with age. For example, the Sanger Institute conducted an elegant study taking multiple biopsies of the eyelid and subjecting them to deep sequencing. They found many mutations traditionally associated with cancer.
Chris – So, the body is full of the genetic hallmarks of cancer all the time, but it doesn’t manifest in even a fraction of people with those changes?
Charlie – Exactly. My colleague James DeGregory at the University of Colorado estimates that a 60-year-old person will have 100 billion cells with mutations commonly associated with cancer. Yet, our lifetime risk of cancer is between one in two and one in three. To give you context, the human body has roughly 30 trillion cells. So, at the cellular level, cancer is incredibly rare, even though 100 billion cells carry these mutations.
What’s happening is that cancer initiation requires a two-step process. Mutations might be necessary but are not sufficient on their own. Instead, a second step is required, often referred to as a promoter step, which can be triggered by chronic tissue inflammation.
For example, air pollution particles taken up by immune cells, like macrophages, can’t be digested. These cells release inflammatory signals that act on stem cells carrying cancer mutations, triggering tumour development.
Chris – So, asbestos exposure is a good analogy here? Asbestos fibres get deep into the lungs, frustrating the immune system, which produces inflammatory signals. If nearby lung cells have random genetic damage, the two factors combine to increase cancer risk?
Charlie – Precisely. Mesothelioma is a prime example of this. The fine asbestos fibres get into the lung and are taken up by macrophages, which release inflammatory signals like interleukin-1 beta. These signals act on cells with mutations—the wrong mutation, in the wrong cell, at the wrong time—resulting in cancer. It’s like a Swiss cheese model, where all the holes line up to cause disease.
Chris – This aligns with findings on drugs like aspirin, doesn’t it? People with colon cancer who take aspirin have a lower chance of recurrence. Does aspirin suppress inflammation, reducing the likelihood of that “one-two punch” Swiss cheese effect?
Charlie – That’s my assumption, though we need more evidence to prove it. But it’s certainly plausible.
Chris – So, should we all take anti-inflammatories to prevent cancer?
Charlie – If only it were that simple! These findings highlight opportunities for intervention. However, we need to identify the key inflammatory regulators where we can intervene. At present, we don’t know what those are. We have some strong clues, and over the next decade, our lab will focus on understanding these nodal regulators of tissue inflammation—essentially, what’s allowing those holes in the Swiss cheese to form.
15:37 - Charlie Swanton: Treating cancer
Charlie Swanton: Treating cancer
Charlie Swanton, Francis Crick Institute
Over the last 5–10 years, researchers in various labs have been studying bacteria that appear to be associated with cancers, particularly those prone to metastasise or spread. Is this just a side effect because an abnormal cell is attracting bacteria, or are the bacteria actively contributing? Some researchers suggest these bacteria may even cause resistance to certain chemotherapies, essentially helping the cancer cells...
Charlie – Yes, I think this is a very interesting and rapidly emerging area of study, with evidence steadily building to support that idea. Let’s start with a well-established bacterial cause of cancer: Helicobacter pylori (H. pylori), which is a very common cause of gastric cancer.
We know, thanks to the work of Barry Marshall and others—who won the Nobel Prize—that H. pylori directly causes gastric cancer. Over the last five years or so, it has also emerged that another bacterium, a so-called PKS-positive E. coli, can cause mutations in the gut. These mutations likely help initiate the early stages of cancer by triggering genetic changes in cells and enabling other tissue inflammatory mediators to drive cancer’s invasive steps.
As you rightly mentioned, we’ve also reported in recent years the association between the gut microbiome and differential responses to therapy, as well as the presence of bacteria within tumour cells. What we currently lack is clear functional evidence of exactly how these processes work. It’s undoubtedly complex. For instance, how does a gut microbe influence the peripheral immune response to therapy? How could it activate or suppress, depending on the type of bacteria, the cellular T-cell response to immunotherapy in distant locations such as the bloodstream or the lungs, far from the gut?
Understanding these processes is challenging, and gathering definitive evidence will take time—but progress is happening quickly. I think this will be a very hot area of research over the next five years.
Chris – Some people describe the microbiome as a hidden organ that we’ve overlooked for far too long. There are around 50 trillion bacteria in the average human gut, secreting a wide array of molecules into our circulation. For example, John Cryan in Ireland has shown that the microbiome is even involved in forming the blood-brain barrier in a developing baby during pregnancy. If it can produce those kinds of signals, it doesn’t seem far-fetched that manipulating the microbiome could influence cancer.
Charlie – I completely agree. If there’s one thing science has taught me over the last 20 years, it’s that you have to believe in what seems impossible. Things that feel like science fiction today often become science fact tomorrow.
Take cancer as an example. Twenty years ago, I didn’t think of it as a systemic disease. Now we know that tumour cells interact broadly with the body. They communicate with the liver to alter metabolism, break down muscle and fat to create building blocks for growth, and even influence neuronal networks. It’s a systemic disease interacting with multiple organs—and the same can likely be said for the microbiome.
Chris – Let’s talk about managing or treating cancer. Understanding the mechanisms of a disease is crucial for developing treatments because it shows us how to disrupt its processes. What have been the major breakthroughs in cancer treatment, especially once the snowball is already rolling?
Charlie – That’s a big question! If we focus on the major advances over the last two decades, during my career in medicine, I’d highlight two game-changing developments.
First, the advent of targeted therapies. These are treatments—small molecules or antibodies—that specifically target abnormalities in cancer cells. For example, mutations in certain genes or overexpression of proteins on the cell surface allow cancer cells to proliferate.
A well-known example is the HER2 oncogene in breast cancer, targeted by the antibody Herceptin. Another example is Imatinib, which targets specific kinases in chronic myeloid leukaemia (CML). These therapies attack the cancer cells while sparing normal cells and have transformed cancer treatment.
The second major breakthrough, without a doubt, is immunotherapy. When I was training in the 1990s, many researchers had given up hope of boosting the immune system to fight cancer. Funding was withdrawn, and the field stalled. But then Jim Allison and Tasuku Honjo showed that there are “brakes” on the immune system—CTLA-4 and PD-1—that can be targeted with antibodies. By releasing these brakes, T-cells can recognise and attack cancer cells.
Clinical trials led by people like James Larkin at the Royal Marsden demonstrated this beautifully in melanoma patients. Today, we’re talking about curing metastatic melanoma, even in cases where it has spread to the brain. Immunotherapies that target PD-1 and CTLA-4 are transforming outcomes.
I vividly remember in 2005 sitting with Professor Martin Gore, a brilliant oncologist, as he lamented how little progress had been made in melanoma treatment during his 40-year career. But within 18 months, the first immunotherapy trials produced spectacular results. Patients achieved long-term remission, and the approach revolutionised how we manage the disease almost overnight.
This is what gives us hope. What seems impossible today can become possible tomorrow. It’s a message of hope for patients and a reminder to all of us in medicine to keep pushing forward.
22:45 - Charlie Swanton: Preventing cancer, and the two-step model
Charlie Swanton: Preventing cancer, and the two-step model
Charlie Swanton, Francis Crick Institute
If the immune system is capable of fighting cancer, why does it need to be coaxed into it. Why not do it by itself?
Charlie – I think it does, but the tumour finds ways to subvert it. One of the key ways the immune system fails to recognise a tumour cell is because the tumour cell downregulates the expression of surface proteins called HLA (human leukocyte antigen), also known as MHC. These proteins essentially allow the body to distinguish between self and non-self.
Due to the processes I mentioned earlier—genetic diversity and selection—you’ve got a sort of predator-prey relationship, where the predator is the immune system and the prey is the tumour cell. The tumour evolves to adapt and evade the immune system by subverting those surface molecules that enable the immune system to differentiate self from non-self. This is one of the mechanisms by which tumours can evade predation by immune T-cells.
Chris – So the solution is simply to switch off that brake on the immune system, and that ought to deal with all cancers? Or do you think some cancers will respond while others remain almost impossible to crack?
Charlie – That’s a great question. The number of tumour types responding to these drugs continues to grow. Even tumour types I would have assumed wouldn’t respond to these treatments—particularly in early disease—are showing sensitivity. For example, recent data shows that patients with oestrogen receptor-positive breast cancer respond to immune checkpoint blockade, even though these tumours typically have relatively few mutations.
This raises important questions about what the immune system is actually recognising in these tumour cells. While mutations are part of what the immune system identifies, there are clearly other factors at play that we don’t fully understand yet.
Chris – As our confidence in gene editing increases, are we moving towards a point where we could think, “We know what’s gone wrong with the cancer cell; we know where those cells are, and we can target them selectively”? Could we use gene editing in situ to address the cancer and any metastatic deposits, or is that too risky?
Charlie – By the time a patient presents with cancer, particularly late-stage cancer, the disease burden can be enormous—hundreds of millions or even billions of cells. The challenge here is delivery: how do you deliver gene-editing technology to such a vast number of cells? It only takes a few cells to escape for resistance to emerge. You would need to target every single cell, and that’s a significant challenge.
Chris – But isn’t that where the immune system comes in? Could we adopt a multi-pronged approach—using gene editing, immune checkpoint inhibitors, and the immune system itself—to attack the cancer on multiple fronts?
Charlie – Yes, that’s potentially the right strategy. But this is still early days. Gene editing is in its infancy, and while it’s hugely exciting, delivery remains one of the biggest obstacles for gene therapy and gene editing technologies. This has been a challenge since my training days, and it continues to be.
Chris – Are we perhaps going about this the wrong way? It feels like we’re trying to close the stable door after the horse has bolted. Shouldn’t we be putting more energy into diagnosing people much earlier and stopping cancer at a stage where it hasn’t yet become billions of cells? Once it’s reached that stage, it’s very hard to turn back.
Charlie – That’s exactly the conclusion many of us have reached. Our work in TracerX, along with research from many other investigators worldwide, has shown that tumours have so many evolutionary paths for growth and adaptation that achieving cures in late-stage disease is extraordinarily difficult. I never say never, but it makes you think: how can we maximise the good we do for the greatest number of patients within a 20-year career?
Right now, we’re focusing on early diagnosis, as you mentioned, but also going one step further—towards prevention. How can we attenuate tissue inflammatory pathways to stop cancer from developing in the first place? Which inflammatory pathways can we block to reduce cancer risk while still enabling the immune system to fight infections? These pathways exist for a reason—they protect us from microbes, viruses, and bacteria. So we need to find subtle ways to prevent cancer without compromising our ability to combat infections.
Chris – During this interview, you’ve mentioned several cases where you’ve completely revised your understanding of how this disease works. If I could wave a magic wand and give you the answer to one big question, what would it be? What would you like to solve before the end of your career?
Charlie – There is one question I’d really love to answer. I mentioned earlier the work of Isaac Berenblum and Alan Balmain on the two-step model of cancer initiation: you need mutations and an inflammatory mediator. The big question is, how do those two collaborate?
What is the inflammatory mediator doing to the stem cell where that cancer-causing mutation resides? I suspect there’s a switch—a mechanism that activates cancer development. If we could identify that switch and find ways to turn it off, we could potentially target the very first step of cancer initiation, even in late-stage disease.
Chris – And when you leave the Crick in the evening, what do you do to switch off?
Charlie – I don’t switch off. I keep thinking about these problems.
Chris – There’s a bottle of Shiraz on your desk. Does that help?
Charlie – I probably shouldn’t admit this, but yes.
Chris – A Christmas present, by the looks of it?
Charlie – Yes, it helps. But even when relaxing, your mind wanders back to these questions. You wake up at 2 a.m. and think, “Eureka, that’s the solution!” Those moments happen less often than they used to 20 years ago, but this job is so exciting. It’s hard not to think about it, even when you’re unwinding.
We spend a lot of time talking to other scientists socially because that’s what we love. This job has real purpose and tangible impact—it’s a privilege to be part of it.
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