Life With “The Most Extraordinary Job”

During his first year of medical school in 1991, Charles Swanton, MBPhD, FRCP, FAACR, FMedSci, FRS, received a call from his father, who said he had lost sensation between his legs. Swanton could not have known that this was the first in a series of events that would have a significant influence on his life and, ultimately, his career.

Swanton’s father, a cardiologist with a deep understanding of science and medicine, suspected there was more to his condition beyond simple saddle anesthesia. It turned out his medical team had told him he had a chordoma at the bottom of his spine, a revelation that devastated Swanton, his younger sister, and his mother, who all assumed the diagnosis was a death sentence or at least would require him to use a wheelchair.

As Swanton’s father was about to undergo surgery, the orthopedic surgeon insisted on a biopsy, something that was not nearly as standard practice as it is today. The biopsy revealed that the tumor was a high-grade B-cell lymphoma that could be treated with chemotherapy and radiation.

Following appropriate systemic treatment, Swanton’s father was cured and able to return to work, treating patients in the National Health Service for another 25 years, and is alive and well over 30 years later, thanks in no small part to the decision by the orthopedic surgeon to do the biopsy. This series of events was a major turning point for Swanton, who realized that a single outspoken medical voice can make a massive difference in a patient’s life.

“All of the research that had gone on [over] the previous 30 to 40 years preceding the date of my dad’s diagnosis led to this hugely successful result thanks to combination chemotherapy and radiotherapy. I thought about all the trials, research breakthroughs as well as research cul-de-sacs, that led up to that point and said to myself, ‘This is something I want to be involved in for the rest of my life,’” Swanton said.

Swanton credits several mentors with helping him pursue oncology and providing guidance and motivation while he completed his medical degree at University College of London. David Gingell, MD, gave a lecture on cell motility that piqued Swanton’s interest in how cells evolved to move in such ways. Swanton said the 2-hour lecture hooked him on cell biology and he said Gingell offered constant support and guidance that contributed to Swanton pursuing a PhD in oncology.

When Swanton was deciding where to study, Anthony Segal, MD, PhD, DSc, MRCP, FRCP, shared his own experience with what made a good project and what sound science looked like in practice. Swanton said Segal pushed him toward pursuing his PhD at Imperial Cancer Research Fund Laboratories, which eventually became The Francis Crick Institute. Here Swanton met Nic Jones, his PhD mentor, who taught him how to approach a scientific question and inspired in him the freedom to think boldly.

During his time as a junior doctor, Swanton worked under the neurogeneticist Nicholas Wood who he says was one of the few clinical academics who truly integrated scientific research with medicine to make discoveries that affect outcomes for patients in the clinic. When it came time to learn the art of practicing medicine, Martin Gore, MD, was Swanton’s mentor and was one of his greatest friends.

Helping to Shape a Rapidly Changing Landscape

Swanton currently serves as the principal investigator and deputy clinical director at the Francis Crick Institute, Cancer Research UK’s chief clinician and is co-director of CRUK’s Lung Cancer Centre of Excellence, chair of personalized cancer medicine at the University College London Cancer Institute, and is a consultant thoracic oncologist at University College London, all in London, England. He has been a first or senior author on over 210 published papers that have appeared in the New England Journal of Medicine, Nature, Nature Genetics, Cancer Discovery, Cancer Cell, Science, and The Lancet Oncology. He has received several honors and awards, including the Stand Up To Cancer Translational Cancer Research Prize, GlaxoSmithKline Biochemical Society Prize, San Salvatore prize for Cancer Research, the Royal Society of Medicine Ellison-Cliffe Medal, Massachusetts General Hospital Cancer Center Jonathan Kraft Prize for Excellence in Cancer Researc, and the MSKCC Paul Marks prize for Cancer Research.

Swanton’s laboratory, the Cancer Evolution and Genome Instability Laboratory, is primarily focused on expanding the understanding of cancer evolution at the genetic level. Leveraging the latest DNA sequencing techniques and functional model system, to assess and understand genetic heterogeneity of cancer cells and predict patterns of tumor evolution. Findings from his laboratory have significantly broadened the understanding of how cancer cytotoxins, chromosomal instability driving loss of human leukocyte antigens and other immune evasion events, cancer genome doubling events, and DNA replication stress play a role in the diversity of tumor cells.

“Visualizing cancer through an evolutionary lens is probably the overarching discovery we’ve contributed to. Meticulous genome sequencing studies from our lab and others have changed my understanding of the disease and framed our entire lab program around evolution and evolution of the disease,” Swanton explained.

Expanding on the concept of intratumoral heterogeneity, Swanton is the principal investigator of the ongoing TRACERx prospective clinical study (NCT01888601) in the United Kingdom with the goal of furthering the understanding of the evolution of non–small cell lung cancer (NSCLC) and how it develops resistance to treatment by gathering detailed clinical, histopathological, tumor genetic and phenotypic information over space and time for each patient. A team of coordinated groups works on the study and findings from the trial have provided insights into neoantigen-directed immune escape, how tumor cell mutations affect T-cell differentiation, and the relationship between body composition and lung cancer–associated cachexia—all while mapping the evolution of NSCLC in the most detailed manner to date. TRACERx, which was initiated in April 2014, is the largest long-term lung cancer study of its kind in the world, with an enrollment of more than 800 patients and each patient receiving 5 years of follow-up.

“In TRACERx, we developed an understanding that the immune system is constantly constraining cancer development from a very early stage,” Swanton explained. “[This study] has taught us that metastatic disease is a formidable force to be reckoned with, incredibly challenging. Based on that, it’s going to be very hard to cure that disease and all patients in my lifetime. So, what can I do to advance care and limit human suffering? Preventing cancer has got to be the way forward.”

This granular approach to studying cancer cells has also led to a deeper understanding of how air pollution contributes to NSCLC, particularly among never smokers. In 2022, Swanton shared data amassed from TRACERx during the European Society of Medical Oncology Congress showing that increased concentrations of particulate matter in the air were associated with an increased risk of EGFR-mutated NSCLC in a large cohort of patients. Findings from Swanton’s group showed that 2.5-μm particulate matter can cause the release of interleukin 1β in lung epithelium and alveolar macrophages, inducing inflammation and driving a cancer stem cell–like state in EGFR-mutant clones.

TRACERx has been able to identify suitable patients for a bevy of other clinical trials evaluating personalized treatment options based on the unique genetic characteristics of their disease, including the phase 1/2 CHIRON (NCT04032847), the phase 2 DARWIN1 (NCT02183883), and the phase 2 DARWINII (NCT02314481) trials. CHIRON, for which TRACERx established the scientific rationale, is examining clonal neoantigen T-cell therapy in NSCLC, DARWIN1 evaluated afatinib (Gilotrif) in patients with EGFR/HER2-mutant NSCLC, and the exploratory DARWINII trial will look to determine the role of various mutations and genomic markers on treatment outcomes with atezolizumab (Tecentriq), vemurafenib (Zelboraf), ado-trastuzumab emtansine (Kadcyla), or alectinib (Alecensa) in patients with relapsed NSCLC.

“For me, in a way, the science of medicine and oncology has become an addiction. I am absolutely enthralled by it… I can’t thinking enough about the challenges we face,” Swanton said. “Answering scientific questions can have such a massive impact on patients’ lives. The answers to those questions can all unravel in front of your eyes. It’s just so beautiful and exciting. I am privileged to be working in this era.”

In November 2022, Cancer Research UK announced TRACERx EVO, a new program headed by Swanton aiming to build on the findings of TRACERx. TRACERx EVO will involve an international consortium of leading experts from Europe and North America enrolling approximately 450 patients with early- and late-stage resectable and unresectable NSCLC and will further investigate the role of air pollution in lung cancer, develop new tools to examine their datasets, and try to deepen the understanding of lung cancer–related cachexia.

Enjoying Life Beyond the Lab

Outside the clinic, Swanton is an avid cyclist who enjoys riding around his native southwest London and frequently makes the 10-mile trek to work by bike in central London. He enjoys meeting people in the multitude of pubs and restaurants and carving out time to escape to the countryside by train. He also loves music and attends concerts any chance he gets and said the music of U2 is particularly resonant for him.

Swanton takes great pleasure in spending time with his 2 daughters, Poppy, aged 20 years, and Chloe, aged 17 years, and commended their independent thinking and strong moral compasses. He is particularly proud of their interest in the sciences: Poppy is studying chemistry at University College London and Chloe plans to pursue biology. Swanton loves their trailblazing nature and emphasized the need for many more women in the sciences.

Beyond his lifelong hometown of London, Swanton likes to spend time outdoors and has had spectacular excursions in South Africa, Zimbabwe, Botswana, Kenya, the Grand Canyon, and Yosemite and Yellowstone national parks. Staying true to his passion, he is fascinated by how evolution has shaped the breathtaking ecosystems of these places.

Swanton hopes to someday visit Central Asia as well as northern and southern China, but making time for that has proved difficult with his jam-packed schedule and high-level responsibilities. But he does not see his near total immersion in his work as a negative.

“I keep saying to myself, ‘I’d like to work hard, live, and play more,’” Swanton explained. “The problem is my work and play are completely interwoven. I love every moment of my job. There’s not a single day I don’t enjoy. I consider myself very fortunate to be in a job that is incredibly rewarding, worthwhile, pays the mortgage, and is enjoyable. Charles Darwin was a gentleman scientist who didn’t have a salary. He lived on personal wealth. If I was like him, I would honestly carry on doing what I’m doing. I wouldn’t stop doing it. It’s the most extraordinary job I could ever imagine.”