The process of cell division, which allows for growth and maintenance, carries the potential for error. When these errors accumulate in genes that control cell growth, cancer can emerge. This presents an evolutionary puzzle, as creatures with more cells and longer lifespans should statistically face a much higher cancer risk. Yet, across the animal kingdom, many large, long-lived species have developed defenses against this threat, offering clues to how nature has navigated this challenge.
The Evolutionary Problem of Cancer
A simple calculation suggests that a large, long-lived animal should be far more susceptible to cancer than a small one. Every time a cell divides, there is a chance of a mutation, and with trillions more cells than a mouse, an elephant undergoes countless more divisions, increasing the opportunities for cancer to arise. This discrepancy between statistical risk and observed reality is known as Peto’s Paradox, named after epidemiologist Richard Peto. He noted that cancer incidence does not correlate with body size or lifespan across species; for instance, a human has a much higher cancer incidence than a blue whale, which has about 1,000 times more cells.
This paradox implies that as certain animals evolved larger bodies and longer lives, they must have also evolved cancer suppression mechanisms. Without such adaptations, the evolution of large, long-lived animals might not have been possible. The study of these natural solutions reveals the different strategies life has employed to manage the threat of cancer.
Genetic Redundancy as a Protective Shield
One of nature’s solutions to the cancer problem involves reinforcing the genetic code. The primary example is found in elephants, which possess a defense system centered on a gene called TP53. This gene produces the p53 protein, often called the “guardian of the genome,” which helps prevent cancer in many organisms.
The p53 protein acts as a cellular supervisor, monitoring for DNA damage. When it detects a problem, it can halt the cell cycle to allow for repairs. If the damage is too severe, p53 triggers apoptosis, or programmed cell death. Humans have one copy of the TP53 gene, and individuals born with one non-functioning version have a greater than 70% lifetime cancer risk.
Elephants, however, have taken this protective system further. Their genome contains 20 copies of the TP53 gene, and this genetic redundancy creates a hyper-sensitive response to cellular damage. With so many copies, the threshold for detecting a threat is much lower.
An elephant’s cell is far more likely to initiate apoptosis in response to minor DNA damage compared to a human cell, which might attempt a repair. This approach ensures that rogue cells are eliminated efficiently, preventing tumors from getting a foothold.
Modifying the Cellular Environment
A different strategy for cancer resistance focuses not on genetics, but on the physical environment surrounding a cell. This approach is exemplified by the naked mole-rat, a long-lived rodent with a high resistance to cancer. These animals almost never develop the disease, a trait not explained by mechanisms seen in elephants.
The secret lies in high-molecular-weight hyaluronan (HMW-HA). Naked mole-rats produce a version of this molecule that is over five times larger than in humans or mice, and it is abundant in the space between cells. This is due to a unique version of the HAS2 gene and lower activity of enzymes that would normally break it down, resulting in a dense substance that fills the tissues.
This abundance of HMW-HA creates a protection known as “early contact inhibition.” The dense matrix makes the cells highly sensitive to crowding. As soon as cells begin to divide and touch one another, HMW-HA sends signals that instruct them to stop proliferating. This mechanism halts uncontrolled cell growth at the earliest stage. When scientists removed HMW-HA from naked mole-rat cells, they became susceptible to cancerous transformation, demonstrating its direct role in their cancer defense.
Lessons from Animal Defenses for Human Health
The study of cancer resistance in animals, a field known as comparative oncology, provides blueprints for new approaches to treating cancer in humans. Nature has run countless experiments over millions of years, and the resulting solutions are a resource for medical innovation.
Understanding the elephant’s reinforced TP53 system, for instance, could inspire gene therapies or drugs designed to make human cells more sensitive to DNA damage. A treatment that mimics the elephant’s hyper-active apoptotic response could encourage our own damaged cells to self-destruct more readily.
Similarly, the naked mole-rat’s use of HMW-HA points toward therapies that modify the cellular environment to make it less hospitable for tumor growth. Developing treatments that increase the stability of hyaluronan around potential tumors could re-establish the contact inhibition that cancer cells override.