Consider for a moment the blue whale. Weighing up to 200 tons, this majestic creature is believed to be the largest animal that has ever existed on planet Earth. It also has a remarkably long lifespan of 100 years or even more.
In theory, the blue whale should be highly susceptible to cancer: It has quadrillions of cells that could acquire the requisite oncogenic mutations, and its extended lifespan provides plenty of time for this to occur. In fact, when researchers applied an equation for estimating human colorectal cancer risk to a whale-sized organism, it predicted that virtually all blue whales would develop this form of cancer by age 80.1 Conversely, the same equation scaled down for mice predicted that they would essentially never get colorectal cancer, even if they lived for 90 years. This is, of course, not the case. Despite their brief lifespans, mice have a one to four percent chance of developing this type of cancer, similar to the human lifetime risk of about four percent.2,3 And while the exact incidence of colorectal cancer in blue whales is not known, it is certainly not 100 percent.
This perplexing phenomenon, now known as Peto’s Paradox, was first described by epidemiologist Richard Peto in 1977.4 Peto’s Paradox is the observation that between species, there is not a strong correlation between cancer risk and body size. At the time, there was relatively little information available on cancer prevalence in non-model organisms, but as comparative oncologists have gathered increasingly detailed data from zoos, aquariums, and veterinarians, Peto’s initial speculation has largely proven correct.
For example, a 2022 study of more than 100,000 animals across nearly 200 different mammal species found that cancer mortality risk was not closely associated with body mass or species lifespan.5 In fact, many of the large-bodied species that they assessed, including the giraffe, bison, and imperial zebra, had extremely low cancer mortality rates.
If we can understand how [different species] protect themselves—how they prevent cancer or keep it under control—we could maybe use this information to develop some methodologies to prevent or treat cancer in humans.
—Orsolya Vincze, French National Center for Scientific Research
“If we can understand how [different species] protect themselves—how they prevent cancer or keep it under control—we could maybe use this information to develop some methodologies to prevent or treat cancer in humans,” said study coauthor Orsolya Vincze, a wildlife cancer researcher at the French National Center for Scientific Research. “Current cancer treatments, like chemotherapy, are generally harmful, not just for the cancer cells, but also for healthy cells… But the natural cancer suppressive or preventive mechanisms that these animals have might provide us with information that could help us develop treatments that are not harmful for healthy tissues and healthy cells.”
To gain greater insight into the factors contributing to varying rates of cancer in vertebrates large and small, an international group of researchers analyzed cancer incidence in 292 species of mammals, reptiles, amphibians, and birds in relation to several different life history traits.6 These included body size, but also litter size, gestation length, growth rate, and metabolic rate, among others. They found that in mammals, longer gestation times decreased cancer risk, and when they used statistical models to control for the effect of gestation time, there was in fact a slight increase in cancer prevalence with increasing body size. However, said study coauthor Zachary Compton, a comparative oncologist at the University of Arizona, these findings don’t necessarily undermine the core idea behind Peto’s Paradox. “The true paradox is not that [large mammals] get less cancers than smaller mammals…but if cancer risk scaled with the number of cells, [these animals] would be overwhelmed with cancer. They still get far less cancer than is predicted by just their mass of somatic cells… These animals obviously have some enhanced cancer suppression mechanisms and so they're interesting to study.”
Many scientists agree: Research groups around the world are combing through the genomes, transcriptomes, and proteomes of animal kingdom giants like elephants and whales, searching for the secrets to a long and cancer-free life.
p53 and the Elephant in the Room
Lisa Abegglen, a comparative oncologist at the University of Utah, has long been interested in translational cancer research. After completing her PhD in immunology and a stint working in drug discovery, she joined the Huntsman Cancer Institute in 2011, where she worked with pediatric oncologist Joshua Schiffman studying Li-Fraumeni syndrome (LFS). LFS is a rare genetic disorder in which patients have only one functional allele of the tumor protein 53 (TP53) gene, instead of the usual two alleles.
p53, the protein encoded by TP53, is a crucial tumor suppressor: In response to DNA damage, it halts the cell cycle, giving the cell time to repair the damage. If the damage cannot be repaired, however, p53 initiates apoptosis, killing the mutant cell. Without two functional TP53 alleles, LFS patients are commonly diagnosed with childhood cancers and have a 90 percent chance of developing cancer before the age of 60.7
Everything changed when Schiffman happened to attend a presentation by cancer biologist Carlo Maley, now at Arizona State University, regarding Peto’s Paradox. Maley and his team had analyzed data from the San Diego Zoo, confirming that large animals had much lower rates of cancer than would be expected, given their size and lifespan.
“He had a graduate student at the time, Aleah Caulin, who was looking into the genome for clues as to why that would be the case,” said Abegglen. “They looked at the elephant because it was a nice example of a very large, long-lived animal that's not getting more cancer… And she found that elephants have extra copies of TP53.” Schiffman, she said, was fascinated, immediately recognizing the parallels between this work and his own studies of LFS. Comparing the molecular machinery at work inside cells with many copies of TP53 and cells with too few copies of this gene could reveal new therapeutic targets for cancer suppression.
Orsolya Vincze studies life history traits and cancer in wildlife.
Tamás Malkócs
After the presentation, Schiffman proposed that they collaborate on just such a project. Schiffman, Abegglen, Maley, and Caulin went on to publish a paper in 2015 showing that African elephants have 20 copies (40 alleles) of TP53, as well as increased sensitivity to DNA damage: When elephant cells were exposed to radiation, they were more likely to undergo apoptosis than typical human cells, and much more likely to undergo apoptosis compared to cells from patients with LFS.8
But what exactly are these elephant TP53 copies doing? “This is a very complicated question. It’s something I have been intensely focused on ever since our first paper was published,” said Abegglen. The canonical form—the original copy—seems to be fairly similar to the version in humans and mice, she said.
“But the extra copies—the retrogenes—are definitely different,” she continued. “They all have premature stop codons. So, when they are expressed as proteins, they do not make a full p53 protein. And [since] that stop codon is within the DNA binding domain, it seems unlikely that they bind to DNA.”
However, this doesn’t mean they have no function, as p53 can induce apoptosis in multiple ways. In one pathway, p53 binds to DNA to initiate transcription of pro-apoptotic genes, such as the aptly-named p53 upregulated modulator of apoptosis (PUMA).9 However, another pathway does not require p53 to act as a transcription factor; instead, it initiates apoptosis by binding to specific proteins at the mitochondria. One of the extra p53 copies observed in elephants seems to operate through this second pathway. When Abegglen expressed TP53-retrogene 9 (TP53-R9) in human cancer cells, the resultant protein traveled to the mitochondria, where it bound to pro-apoptotic proteins, eventually leading to cell death.10
Along with the scientists at Peel Therapeutics, a company founded by Schiffman in 2015, Abegglen is working on translational strategies for applying elephant p53 to human health. In a poster presentation at the American Association for Cancer Research meeting in 2024, the researchers demonstrated that lipid nanoparticles could be loaded with mRNA encoding elephant p53 or p53-R9 for delivery to cancer cells, effectively inducing apoptosis in vitro.11 However, there’s still at least one major hurdle standing in the way of the translational potential. “Too much p53 in a normal cell will also induce apoptosis,” said Abegglen. “But if we could target just the tumor cells, then it's a very promising therapeutic approach. And there are a lot of people trying to figure that out.”
Zachary Compton studies the development of cancer in species from across the tree of life.
Hannah Harken
As the “guardian of the genome,” p53 is an excellent starting point for researchers seeking to understand how animals avoid cancer, but it might not be the only genomic trick that elephants possess. Vincent Lynch, an evolutionary biologist at the University at Buffalo, is conducting a broader exploration of the genomes of elephants to identify other factors that could contribute to their remarkable abilities.
“You can't just have one mechanism or one mutation that makes you long-lived and cancer resistant,” said Lynch. “You need many.”
In addition to multiple copies of TP53, Lynch found that elephants have several copies of leukemia inhibitory factor (LIF), a gene with both pro- and anti-oncogenic functions, depending on the context.12,13 Lynch and his research team investigated the functions of the extra LIF copies in elephant cells and determined that one (LIF6) played an important role in triggering apoptosis in response to DNA damage, suggesting that it likely functions as a tumor suppressor.
To identify other mechanisms, Lynch and his team scanned elephants’ DNA for genes with signatures of positive selection and rapid evolution. In a recent preprint, they identified hundreds of genes with these characteristics; this set of genes was enriched for functions related to cell cycle regulation, cell death, growth factor signaling, and immune function, which are all processes potentially involved in cancer development or resistance.14
Genetics of Cancer Resistance in Elephant Relatives
Lynch is also interested in comparing elephants to other Afrotherians, a mammalian superorder that includes aardvarks, hyraxes, tenrecs, and sea cows. “What's really interesting is that in the common ancestor of elephants, hyraxes, and manatees, in that lineage there are a whole bunch of tumor suppressor genes that got duplicated.” Today, the hyrax is quite small—about 3kg—and at 480kg the manatee is certainly large, but perhaps not truly gigantic. However, they both have much larger extinct relatives; Titanohyrax was estimated to weigh more than 1,000kg and Stellar’s sea cow was even larger at 8,000kg.15
Vincent Lynch analyzes the genomes of elephants, whales, manatees, and other outsize species.
Douglas Levere, University at Buffalo
The genomes of these Afrotherians—both giants and relatives of extinct giants—display many different gene duplications and losses that may also play important, although underexplored, roles in cancer resistance. For example, both elephant and manatee genomes had duplications of genes that can function as tumor suppressors, including serine/threonine kinase 11 (STK11) and bromodomain containing 7 (BRD7), with well-conserved sequences, suggesting they may produce functional proteins instead of simply being pseudogenes.15 In a recent preprint, Lynch and his team also identified several genes in elephants, hyraxes, and manatees that have been pseudogenized or lost altogether.16 Some of these genes are involved in inflammatory cell death programs—necroptosis and pyroptosis. These losses may protect against cancer, as necroptosis may promote metastasis, but will need further investigation as inflammatory cell death can have both pro- and anti-cancer functions in different contexts.17
Indeed, there is only so much that researchers can learn from genomes alone. To study the function of a specific gene variant, researchers can delete the gene from cells where it normally belongs, or they can insert the gene into a human or a mouse cell and observe how these manipulations affect a cell’s ability to pause the cell cycle, repair DNA damage, or initiate apoptosis when necessary. In vitro experiments can provide insights into cell-autonomous processes related to cancer, like proliferation and cell death, but if scientists want to explore processes that require interactions with other cells, like immune cells, transgenic animals may be needed.
While it’s not feasible—or ethical, some scientists argue—to genetically manipulate an elephant, there’s a lot that scientists could learn from smaller, short-lived model organisms. “There are transgenic lines of zebrafish whose genomes have been edited in such a way that they're prone to different kinds of cancers,” said Lynch. “So what happens if we put the gene in these zebrafish that are that are likely to get cancer? Can we prevent it? Or delay its progression?”
“The model that's really cool and that I really want [to experiment with] is African turquoise killifish,” said Lynch. This species is one of the shortest-lived vertebrates, with many only living about two months in the wild. “Some strains get a lot of cancer, so can we make them live longer, better, healthier lives if we put elephant genes or whale genes or armadillo genes into them?”
Anticancer Inspiration from Animal GiantsMammal body size varies tremendously, from the Etruscan shrew, which weighs less than two grams, to the blue whale, which can grow to an impressive 200 tons. Yet mammals with millions of times more cells than their tiny relatives aren’t proportionally more likely to develop cancer, even though their lifespans are usually much longer. Researchers are currently studying the genetic and proteomic quirks of these giants from many different mammalian orders, hoping to discover new ways to fight this deadly disease.  modified from © istock.com, johnnylemonseed, Zhenyakot, Bullet_Chained, blueringmedia, Anna Bliokh; designed by Janette lee-latour | |
African elephant: The African elephant is one of the most intensively studied large mammals in the context of cancer resistance. Within its genome, scientists have identified multiple copies of the tumor protein 53 (TP53) and leukemia inhibitory factor (LIF) genes, both of which play important roles in tumor suppression, including the initiation of apoptosis in cells with DNA damage. |  © istock.com, blueringmedia |
West Indian manatee: A recent preprint found that manatees, along with their relatives the dugongs, hyraxes and elephants, have lost several genes involved in necroptosis and pyroptosis, including mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting protein kinase 3 (RIPK3). Since necroptosis can promote tumor metastasis, researchers proposed that these losses may be protective. |  © istock.com, johnnylemonseed |
Capybara: While the capybara is smaller than many other giants of the animal kingdom, at 65kg, it dwarfs every other rodent species, many of which tip the scales at only a few hundred grams, or even less. The capybara genome contains expansions of gene families melanoma antigen family B5 (MAGEB5), and granzyme B (GZMB), which play important roles in pathways related to T cell-mediated tumor suppression. |  © istock.com, Bullet_Chained |
Bowhead whale: Bowhead whales may have multiple mechanisms of cancer resistance. In preprints that analyzed the genome and the cells of bowhead whales, researchers identified a retroduplication of the gene cyclin-dependent kinase inhibitor 2C (CDKN2C), which regulates the cell cycle, and elevated levels of cold-inducible RNA-binding protein (CIRBP), which is involved in DNA repair. |  © istock.com, Zhenyakot |
Enhanced DNA Repair Could Help Whales Dodge Cancer
For scientists studying cancer resistance in elephants or other large land animals, zoos provide an excellent source of data, including veterinary records and DNA. However, noted Vincze, who coauthored the 2022 study on cancer in hundreds of mammal species, “The zoos have a limitation, because they cannot keep marine mammals that have huge body sizes—of course they cannot keep a four-ton blue whale in a city! And these animal species must, by definition, have very strong cancer defenses because of the extremely large body sizes and pretty remarkable lifespans. So, we missed this branch of the phylogeny in our database simply because it’s inaccessible.”
I'm really, really excited to start digging into the genomes of these animals with my bioinformatics collaborators to identify what are the potential mechanisms of cancer defense in these animals.
—Lisa Abegglen, University of Utah
Fortunately, repositories like the San Diego Frozen Zoo have established cell lines for many species, including some whales, allowing researchers to study anti-cancer factors at the genetic and cellular levels even when they don’t have access to the whole organism. In other cases, researchers are able to obtain cells from skin biopsies taken in the wild. Intriguingly, this research on whale cells has revealed that these marine mammals don’t appear to have the TP53 duplications that are putatively protective in elephants, suggesting they use alternative cancer-resistance strategies.18
A preprint by Lynch’s research group analyzed the genome of the bowhead whale—the longest-lived mammal—and identified duplications of cyclin-dependent kinase inhibitor 2C (CDKN2C), which regulates the cell cycle.19 “One of the ways that you can potentially evolve cancer resistance is by changing the cell cycle,” said Lynch. “There are checkpoints at different parts of the cell cycle, where the cell sort of self-surveils to check that everything is okay before it moves on to the next step.” The extra cell cycle regulator, he said, could make it more difficult for a potentially cancerous cell to overcome these key checkpoints.
Several lines of evidence also suggest that whales have increased DNA repair capabilities. Bowhead whale genomes have duplications of proliferating cell nuclear antigen (PCNA), which is important for DNA synthesis and repair; transcriptomic analysis of kidney and liver cells from a grey whale indicated high levels of expression of mRNA transcripts involved in DNA repair pathways.20,21 And while human lung cells exhibit decreased ability to perform high-fidelity DNA repair after exposure to a potent carcinogen, right whale lung cells maintained DNA repair processes when they were exposed to this same chemical.22
African elephant dermal fibroblasts engineered to express cancer-causing genes: TERT (green), mutant HRAS (red), or both (yellow).
Yingpu Tang, University at Buffalo
In a preprint recently posted by an international collaboration of dozens of researchers, scientists also found that bowhead whale cells were much better at repairing double-strand breaks in DNA than cells from cows, mice, or humans.23 Compared to the other mammals, whale cells had elevated levels of cold-inducible RNA-binding protein (CIRBP), which is upregulated in response to cellular stressors and is involved in DNA repair. Crucially, when researchers overexpressed whale CIRBP in human cells, DNA repair efficiency increased; a change not observed when they overexpressed human CIRBP. While more research is needed, this may represent a new therapeutic target for cancer prevention.
Exploring More Animal Genomes to Fight Cancer
For many other large species, investigations have only just begun but have still provided glimpses into other potential strategies. The genome of a capybara, a rodent that is at least one or two orders of magnitude larger than most other species in its order, contains expansions of gene families melanoma antigen family B5 (MAGEB5) and granzyme B (GZMB), which play important roles in pathways related to T cell-mediated tumor suppression.24
Abegglen, who collaborated with Compton and dozens of other researchers on the 2024 analysis of cancer across vertebrates, said that this study revealed extremely low cancer rates in species that had not previously been studied in the context of cancer, including some primate species. “I'm really, really excited to start digging into the genomes of these animals with my bioinformatics collaborators to identify what are the potential mechanisms of cancer defense in these animals, and then do the functional studies to validate those genomic discoveries,” she said. “The primates are particularly interesting because they're closely related to us, so whatever we discover in the primates is potentially even more translatable.”
Compton also noted that while scientists can learn a lot from species with incredibly low cancer rates, there are also potentially valuable lessons to be learned from species in which the 2024 study identified unexpectedly high rates, such as ferrets or opossums. These animals could help researchers learn about the effects of copy number in cancer-promoting genes or evaluate the oncogenic potential of the viruses these species carry. “In comparative oncology, the interesting discoveries to be made are not confined to an elephant,” said Compton. “There's stuff to be learned all over the map.”
- Caulin AF, Maley CC. Peto’s Paradox: Evolution’s prescription for cancer prevention.Trends Ecol Evol. 2011;26(4):175-182.
- Karim BO, Huso DL. Mouse models for colorectal cancer.Am J Cancer Res. 2013;3(3):240-250.
- American Cancer Society. Key Statistics for Colorectal Cancer. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
- Nunney L. The real war on cancer: The evolutionary dynamics of cancer suppression.Evol Appl. 2013;6(1):11-19.
- Vincze O, et al. Cancer risk across mammals.Nature. 2022;601(7892):263-267.
- Compton ZT, et al. Cancer prevalence across vertebrates. Cancer Discov. 2025;15(1):227-244.
- Cleveland Clinic. Li-Fraumeni Syndrome. https://my.clevelandclinic.org/health/diseases/22073-li-fraumeni-syndrome
- Abegglen LM, et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans.JAMA. 2015;314(17):1850-1860.
- Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001;7(3):683-694.
- Preston AJ, et al. Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria.Cell Death Discov. 2023;9(1):1-11.
- Sanborn M, et al. Lipid nanoparticles as an efficient transfection method for the delivery of elephant TP53 and retrogene9 into osteosarcoma cells.Cancer Res. 2024;84(6_Supplement):3166.
- Vazquez JM, et al. A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage.Cell Rep. 2018;24(7):1765-1776.
- Wang J, et al. Leukemia inhibitory factor, a double-edged sword with therapeutic implications in human diseases.Mol Ther. 2023;31(2):331-343.
- Bowman J, Lynch VJ. Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants.bioRxiv. 2024.02.27.582135.
- Vazquez JM, Lynch VJ. Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk.elife. 2021;10:e65041.
- Birkemeier M, et al. Pervasive loss of regulated necrotic cell death genes in elephants, hyraxes, and sea cows (Paenungualta). bioRxiv. 2024.04.04.588129.
- Qin X, et al. The role of necroptosis in cancer: A double-edged sword?Biochim Biophys Acta Rev Cancer. 2019;1871(2):259-266.
- Tollis M, et al. Return to the sea, get huge, beat cancer: An analysis of cetacean genomes including an assembly for the humpback whale (Megaptera novaeangliae).Mol Biol Evol. 2019;36(8):1746-1763.
- Vazquez JM, et al. A CDKN2C retroduplication in bowhead whales is associated with the evolution of extremely long lifespans and alerted cell cycle dynamics.bioRxiv.2022.09.07.506958.
- Keane M, et al. Insights into the evolution of longevity from the bowhead whale genome.Cell Rep. 2015;10(1):112-122.
- Toren D, et al. Gray whale transcriptome reveals longevity adaptations associated with DNA repair and ubiquitination.Aging Cell. 2020;19(7):e13158.
- Browning CL, et al. Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells. Toxicol Appl Pharmacol. 2017;331:18-23.
- Firsanov D, et al. DNA repair and anti-cancer mechanisms in the long-lived bowhead whale.bioRxiv. 2024.11.05.539748.
- Herrera-Álvarez S, et al. How to make a rodent giant: Genomic basis and tradeoffs of gigantism in the capybara, the world’s largest rodent.Mol Biol Evol. 2021;38(5):1715-1730.
