Titans of Science: Charlie Swanton
PodcastsThe Naked ScientistsTitans of Science: Charlie SwantonWhere are we in the fight against cancer?28 January 2025It’s our final Titans of Science offering of this series, with world-leading cancer expert. . .
PodcastsThe Naked ScientistsTitans of Science: Charlie SwantonWhere are we in the fight against cancer?28 January 2025It’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…Charlie Swanton: What is cancer?Charlie Swanton, Francis Crick InstituteCharlie 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. Charlie Swanton: Cancer's Swiss cheese effectCharlie Swanton, Francis Crick InstituteThe 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.