Peto's Paradox: Why do larger animals with long lifespans have a lower cancer rate than smaller animals with shorter lifetimes and fewer cells? - Researching popular hypotheses on how to solve the paradox

Research Peto's Paradox and then research some popular hypotheses on solving it, such as the following: - Evolution - Hyper Tumors - Metabolic Rates

After researching these, wrap up the project with a quick section on what it would mean for human cancer treatments

What is Peto's Paradox?

• Made in 1977
• Epidemiologist Sir Richard Peto observed that cancer rates in larger animals do not correlate with what they should be. Larger animals with longer lifespans should have a higher probability of carcinogenesis in their lifespan than smaller animals.
  • Mice have a few billions of cells, but larger animals have trillions and much longer lifespans. This should mean that there's an increased risk of carcinogenesis, but there isn't. Why?

Sir Richard Peto

• Age 82, Emeritus Professor of Medical Statistics and Epidemiology
• Widely known for cancer research and the health effects of smoking and tobacco.
• Awards
  • Guy Medal in Silver (1986)
  • Canada Gairdner International Award (1992)
  • Louis-Jeantet Prize for Medicine (1997)
  • Prince Mahidol Award (2000)
  • Royal Medal (2002)
  • Charles S. Mott Prize (2002)
  • King Faisal International Prize (2005)

What could be another factor determining the difference in cancer rate?

• Wildlife, such as whales and elephants, live much more natural lives than humans nowadays, with their diets and lifestyles. Animals living in the wild also engage in more physical activity than humans.
• Humans have more pollution and radiation in their environments than animals.
• From 1983 to 1999, the cancer rate in whales in the St. Lawrence River increased to 27%, one of the highest ever seen in nature. This could suggest that cancer rates also heavily rely on things like pollution.

How does cancer start?

• Cancer starts in the nucleus of the cell. Genes inside the nucleus are in charge of controlling how the cell grows, works, divides, or kills itself. When DNA is damaged, genes can mutate. Gene mutation can be inherited, develop over time, or develop due to things like pollution or radiation.
• Proto-oncogenes are normal genes that control the cell cycle, and when mutated, they become oncogenes, which cause uncontrollable cell growth and division.
• Against oncogenes are tumor suppressor genes, which essentially monitor the cell cycle and halt its progression to fix DNA, prevent cancer or uncontrollable cell division. When mutated, they stop keeping an eye on the cell cycle.
  • One very important gene is the TP53 gene, the "guardian of the genome." It produces the p53 protein and is mainly responsible for aptosis and repair. Lots of cancer starts from mutations in the TP53 gene.
• Mutated genes inside the nucleus interfere with how instructions to the cell are given. These create cancerous cells, which grow and divide uncontrollably.
• Many cancerous cells make a tumour, which can either stay benign (non-cancerous) or become malignant (cancerous), which spreads throughout the body with a process called metastasis, getting nutrients from blood vessels.
• Angiogenesis forms new blood vessels to connect to the tumor.

Popular Hypotheses on how Peto's Paradox happens

• Evolution
• Hyper tumors
• Metabolic rates

Evolution

Evolution plays a key part in solving Peto's Paradox, providing various mechanisms for solving the paradox.

• What is evolution?
  • Evolution is the change in the characteristics of animals over time.
  • Natural selection is when animals better suited to their environment live, and others not so suited die out.
  • Evolutionary pressure is any factor that changes a being's reproduction/way of life.
• Multicellularity and evolution
  • When animals developed multicellularity and grew, they needed to evolve to fight against cancer. Animals that didn’t keep up with evolutionary pressure died out. Natural selection favored genes that would be best suited to larger animals.
• An example of evolutionary pressure is how elephants possess 20 copies of the vital TP53 gene, as opposed to the singular one humans have. The TP53 gene is very important to tumor resistance and heavily contributes to the difference between elephant and human cancer rates. The elephant's body's defense system has much more backup than a human's.
• How reliable is this theory?
  • This theory is pretty reliable and backed up by clear research.

Hyper Tumors

The hyper tumor theory is a newer theory on solving Peto's Paradox.

• What are hyper tumors?
  • Hyper tumors are tumors on tumors. The word "hypertumors" comes from "hyperparasites", which are parasites on parasites.
• Hyper tumor formation
  • Hyper tumors are formed when tumors compete and rebel against themselves- "cheater" cells in a tumor go against the original cancerous tumor and create their own force against it. They feed off the same blood flow that the original tumor formed with angiogenesis and exploit the connections, leading to the original tumor starving off and dying.
• How does this relate to Peto's Paradox?
  • This theory suggests that larger animals do often get cancerous tumors, but the tumors kill themselves off before they become fatal.
  • Smaller animals like mice are affected much faster by tumors, as tumors take up so much of their body mass. In these small animals, hyper tumors do not have a lot of time to form. However, tumors in larger animals like whales need much more time to develop fatally. In the time it takes for them to develop and actually affect the animal, hyper tumors have already stopped it.
• How reliable is this theory?
  • This theory is fairly new and not medically proven. It is definitely not one of the more reliable theories for solving Peto's Paradox.

Metabolic Rates

One theory to explain Peto’s Paradox is the metabolic rate hypothesis.

• What is metabolism?
  • Metabolic rate is the rate at which your body burns energy.
• What is the correlation between metabolism and cancer?
  • Higher metabolisms generate oxygen radicals, which contribute to genetic mutations and damage DNA. As we already know, genetic mutations lead to uncontrolled cell division and cancer.
• How does this relate to Peto’s Paradox?
  • Larger animals have lower metabolic rates than smaller animals, so their bodies are less energetic and calmer. This means that they don’t generate as many oxygen radicals, which ultimately leads to fewer genetic mutations.
  • Higher metabolic rates are more prone to cancer.
• How reliable is this theory?
  • This theory is pretty medically proven, but metabolic rates would only be one factor in the lowered cancer rates.

What does this mean for human cancer research?

• Peto's Paradox helps researchers explore how different animals have different cancer-resistant mechanisms, and how we can take information on what systems other animals use to help aid our own cancer research or cancer treatment. For example, knowing that TP53 in elephants aids them with tumor supressing can help develop new cancer treatments and drugs.

Scientists are still researching solutions to Peto's Paradox.

The cancer mortality rate for elephants was found to be less than 5% compared with a cancer mortality rate for humans of 11% to 25%. -https://pmc.ncbi.nlm.nih.gov/articles/PMC4858328/

For example, scientists have discovered that elephants, which have a cancer rate of only 5%, have about 20 copies of a tumour suppressor gene called TP53, while humans have only one. The p53 protein produced by this gene promotes DNA repair or self-destruction of the defective cell, and thus prevents the onset of cancer. When this gene is inactive, as in 50% of human cancer cases, protection against cancer is reduced. In elephants, if one copy of the gene becomes inactive, the result is not overwhelming since the other 19 copies can take over. -https://baleinesendirect.org/en/study-whale-to-beat-cancer/

From 1983 to 1999, the cancer rate among belugas in the St. Lawrence River was 27%, which is the highest rate among wild animals, according to a study by Daniel Martineau and Pierre Béland. -https://baleinesendirect.org/en/study-whale-to-beat-cancer/

For instance, cancer risk, which is 11–25% in the human population, is not vastly different between mice and humans. In contrast, cancer risk was estimated to be 5% in elephants [5]. -https://link.springer.com/article/10.1186/s12915-017-0401-7

Peto’s Paradox suggests that large, long-lived animals such as the blue whale (Balaenoptera musculus) have evolved mechanisms capable of suppressing cancer 1,000 times better than humans. Research on how these large animals are suppressing cancer holds the promise of dramatic improvements in cancer prevention for humans. -https://pmc.ncbi.nlm.nih.gov/articles/PMC3060950/

Larger animals are less prone to cancer due to years of evolving and changing, and their body size is far more compatible with surviving tumors. Smaller animals with fewer cells are more likely to get cancer due to their fast metabolic rates and small body sizes. Although in theory it seems like larger animals should be more prone to cancer, their body mechanisms are way more compatible.

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I would like to acknowledge my teacher for encouraging me and my mother for helping me understand genetics. I am grateful for all the support I got working on this project.