A bowhead whale paints a striking image of endurance. Some individuals have been found carrying harpoons from failed hunting attempts nearly two centuries ago in a testament to their extraordinary longevity.

Yet, despite a life span of over 200 years and possessing around a thousand times more cells than humans, bowhead whales remain remarkably resistant to cancer. How these giants maintain such longevity and mass without succumbing to malignant disease challenges our understanding of ageing and cancer biology. The apparent contradiction between body size, longevity and cancer incidence has come to be known as Peto’s paradox. For Alex Cagan, Lecturer at the University of Cambridge and the Wellcome Sanger Institute, it’s a paradox that presents an opportunity.

Alex is an evolutionary biologist studying somatic evolution across diverse species to help better understand cancer and ageing. At the very core of Alex’s research lies the simple tenet that perhaps evolution has already solved the problem of cancer, and it’s time for us to take stock. “Species, such as the whale, have evolved for millions of years to be very large, live long lives and have had to face the challenge of how to resist cancer. Evolution can be incredibly creative with its solutions. If we can understand what those solutions are, we could potentially transform cancer risk in humans.”

“We’d like to take tissues from species like elephants, whales and naked mole rats of different ages, and look at what’s happening to cells with mutations that are known to be drivers of cancer,” he says. “Are they spreading the same way? Once they occur, do they remain static and avoid cell division? Are they targeted for destruction? Do they spread, but for some reason, never transform?”

Driver mutations tell only part of the story. Cancer is also shaped by how cells move and interact in space. Tissue and cell architecture, the mixture of cell types and local signalling pathways all influence whether a mutation will expand or remain dormant. In some cases, expanded clones increase the likelihood of acquiring additional mutations – a cascade effect that drives cancer progression.

Yet not all clonal expansions are dangerous. Studies of normal tissues, such as the oesophageal epithelium, suggest that certain mutations, like those in NOTCH1, may actually be protective. “Not all paths lead to cancer,” Alex notes, “and some mutations can push cells down trajectories that reduce risk.”

Environmental exposures further complicate this picture. Factors like inflammation, pollution or diet can themselves be mutagenic or act as promoters for cells with existing but quiescent mutations leading to clonal expansion and increased cancer risk. By combining insights from spatial dynamics and understanding of selective pressures and environmental influences, it is becoming possible to start to map the evolutionary trajectories of cells and understand how those trajectories vary between tissues, individuals and species.

For Alex, the benefits of a comparative approach here are clear as day.  Examining normal tissues offers an even richer perspective on how these creatures naturally suppress cancer. “As they age, do these cancer-resistant species have similar mutational landscape to us? If it’s identical, that would suggest that clonal expansions aren’t key to tumour development. But if their landscapes look completely different, it might indicate that stopping clonal expansion early or limiting mutation accumulation is important to prevent cancer.” Understanding how they avoid cellular expansions containing mutagenic clones could reveal strategies that might one day be replicated in human cells, preventing cancer before it arises.

“In the next five to ten years,” Alex states with a beat of confidence, “we could really be quite certain about how some of these species are resisting cancer.”

The ‘how’ of harvesting samples

For some, the idea of using giant animals as model organisms might sound like too lofty an aspiration. Indeed, with the air of someone well-acquainted with setbacks, Alex recalls the “many, many challenges of working with these models.”

The quest to source samples requires an international, multi-organisational effort. “We work with groups who collect tissue from whales when they wash up on the beach,” says Alex. “There’s the UK Cetacean Strandings Investigation Programme who do necropsies to try and learn more about why these huge animals are beaching.” Another team he works with in France has set up a wildlife cancer network to collect tissues and better understand cancer rates in different models and how this relates to human influences, like pollution.

Alex also describes the challenge of knowing the age of the animal from which the tissues derive. “This is crucial to compare their yearly mutation rate to humans,” notes Alex. “We are exploring the use of epigenetic clocks to estimate age based on the knowledge that epigenetic mutations accumulate at regular time intervals in mammalian species.”

Until this methodology is refined, Alex will continue collaborating with institutions such as the Zoological Society London to first complete this work in zoo animals, with the hope of comparing this to wild populations in the future. Other than answering how large, long-lived species resist cancer, the comparison between wild and zoo animals allows Alex and his team to get at a second question – how is the environment influencing cancer rates?

Despite large strides in genomics, one notable gap is our limited understanding of natural genetic variation in non-human species. As Alex explains: “This would be helpful when we’re looking for rare mutations in a single cell or group of cells. Without it, researchers risk mistaking artefacts introduced during genetic amplification for genuine mutations.” This gap though is starting to close. “New initiatives are building databases of genetic diversity across species, says Alex. “Among them is the Bat1K Project, which will hopefully shed some light on why many bat species live remarkably long lives.”

Dissecting the methodology

In many ways, sequencing the DNA of these unique model species is not so different from the process in humans. “First, you take tissue sample from biopsies or necropsies. Then, you fix those in a fixative called PAXgene. Says Alex. “This fixative maintains the tissue quality but avoids cross-linking the DNA so you can still get clean tissue sections when you set them in paraffin wax.” He then uses laser capture microdissection to isolate specific cells from a mixed population before extracting the DNA ready for sequencing.

Among the most powerful developments in genomics is duplex sequencing, an advanced next-generation sequencing method that error-corrects by comparing both strands of a DNA molecule. “This is a really accurate method of sequencing, meaning that we can trust a mutation is genuine even if we only see it in a single molecule of DNA,” explains Alex. The benefits of duplex sequencing are many, but crucially, it opens the door to studying mutations in cells long perceived as out of reach, such as non-dividing cells. “In theory, we can look at any cell type, from any tissue and potentially, any species,” Alex says.

His vision is to extend this work beyond mammals to other vertebrates. “We want to lay the foundation for a really broad scale comparative oncology approach that will allow researchers to scrutinise mutations, clonal dynamics and cancer development across diverse species.”

Looking forward

Alex’s walk through his research and vision for the future highlights the intricacies and difficulties of trying to trace cancer development and resistance grounded in comparative oncology. Which mutations can drive cancer, how can clonal landscapes unleash or restrain their potential and what environmental factors can tip the balance toward or away from their expression?

It’s clear Alex does not shy away from this daunting task. Rather, he is inspired by the huge potential held in the untapped knowledge hidden in the animal kingdom.

“I really think it’s one of the most valuable but underappreciated tools that we have in biology, in nature and in life in general.”