The most likely time that a cell will undergo malignant transformation leading to clinical cancer is when it undergoes division, i.e., going from one cell to two. In theory, as cells in different organs and various animals and organisms undergo cell division, they have roughly the same risk of a mutation leading to cancer. It would be reasonable to assume that animals with more cells have a higher risk of developing cancer. This is true in dogs where larger breeds have a higher risk of cancer than smaller breeds. At least some evidence shows that the same risk is in play in humans, with taller humans potentially having an increased risk of cancer compared to shorter individuals. Interestingly, although this correlation of body size and cancer risk exists within a species, there does not appear to be a correlation between body size and cancer risk between species. This lack of correlation between size and cancer risk between species is referred to as “Peto’s Paradox.”
One obvious explanation for this paradox would be an increased number of genes known to suppress the growth of new tumors (tumor suppressor genes). BRCA1 and BRCA2 are examples of tumor suppressor genes. However, they are not present in an increased number in larger species. One gene that fulfills these criteria is the LIF6 gene (leukemia inhibitory factor). Most mammals have a single LIF6 gene. However, the manatee and the African elephant contain between 7 and 11 additional copies of this gene. Elephants have a cancer mortality rate of 4.8% compared to humans who have between 11% and 25% mortality rate. The extra copies of the LIF6 genes in elephants could alone account for the mammal’s reduced cancer risk. Scientists believe that most of the duplicate copies of the LIF6 gene were once pseudogenes. Pseudogenes were once functional genes that became nonfunctional. Over 60 million years through the act of mutation, the gene has been resurrected (zombie gene) along the timeline from African and Asian elephants, wooly and Columbian Mammoth, and the straight tusk elephant—the American Mastodon.
The LIF6 gene is not the only tumor suppressor gene present in abundance in elephants. Most mammals, including humans, have a single copy of the TP53 gene. Elephants have 20 copies of this gene. It is thought that the TP53 genes originated from pseudogenes and are therefore also considered zombie genes. It is even believed that the TP53 gene and the LIF6 gene act together to suppress damaged DNA to stop cancer growth.
Do humans have zombie genes?
Most scientists believe that there are over 10,000 pseudo or zombie genes. The PON1 gene is a pseudogene present in certain aquatic mammals. It is thought to have lost its function eons ago, appearing to have given these mammals an evolutionary advantage in oxygen regulation when at depth. Humans have a PON1 gene thought to be associated with breast cancer risk. Most importantly, humans have a single copy of the TP53 gene and LIF (as opposed to LIF6 in animals) gene. Do these two genes represent another opportunity to make up the secret sauce that together may head off cancer before it becomes clinically evident? There are currently gene insertion techniques that, in theory, may help us increase the number of these tumor suppressor genes in humans as it has done naturally in elephants and manatee.
The Caveat: The Rule of Unintended Consequences
Unfortunately, recent investigations have pointed to the protein produced by the TP53 gene (called P53 protein) as potentially having an essential role in the aging process and neurodegenerative disorders such as Alzheimer’s disease. Death of brain cells observed in models of cerebral ischemia, stroke, and traumatic brain injury have been noted to be associated with an increase in the P53 level. If this is the case, at least in theory, adding additional copies of TP53 genes could potentially increase the risk of neurodegenerative brain disease.