By Ted Gansler, MD, MBA, MPH
The DNA of every plant and animal contains the instructions for the chemical reactions that take place in its cells and is essentially the chemical blueprint of that organism. Some of those chemical reactions control how, when, and where cells grow.If those instructions are damaged or deleted, cells can grow and spread abnormally, leading to the diseases we know as cancer. Much of the recent progress in oncology is based on progress in understanding the changes to certain genes in our DNA that cause cancer.
A recent study by researchers from the University of Utah and their colleagues at several other institutions explains how genes in elephants’ DNA might reduce their risk of developing cancer. The elephant gene in question, TP53, is also present in humans, and is damaged or deleted in more than half of all human cancers.
Why elephants matter to cancer researchers
Every time a cell divides, it needs to copy its DNA so that both of the new cells have a full copy of the genetic instructions they need. Cells divide for 2 main reasons – to replace damaged or worn-out cells, and so the plant or animal can grow larger. But, every time DNA is copied, there is a chance of errors occurring. DNA errors (which scientists call mutations) can also be caused by certain cancer-causing chemicals and ionizing radiation. Cells have special enzymes that repair most of their damaged DNA, but once a cell divides, it’s pretty much too late to fix these DNA mistakes. If the DNA mistakes involve genes that control cell growth, that cell can start heading along the path to malignancy. Based on this understanding of mutations and cancer, scientists have wondered whether animals with a lot of cell division (those that reach a large size and live for many years) are more likely to develop cancer than small, short-lived animals.
For this reason, the first step in the current study was for the researchers to analyze information on how common cancer occurs in 36 species of mammals. This analysis was based mostly on autopsies of zoo animals, and the interesting result is that there isn’t any apparent relationship between these animals’ lifespan or size and their risk of developing cancer.
The next step was for the researchers to study the DNA from a species with an especially impressive combination of size and longevity – elephants – to take a close look at genes likely to be involved in causing cancer (oncogenes) or protecting them against cancer (tumor suppressor genes). Most of the elephants’ oncogenes and tumor suppressor genes were similar to those of humans, with one very notable exception – the TP53 tumor suppressor gene. Here’s where the story gets even more interesting. The function of this gene is to help cells fix their damaged DNA, by activating DNA repair enzymes, by slowing down cell division so these repair enzymes have enough time to do their work, and by activating a self-destruction pathway when a cell’s DNA is too badly damaged to be repaired (this destroys individual cells that are damaged, not the entire animal). If these TP53 genes become mutated and unable to do their job, mutations of other important genes caused by chemicals or radiation or random copying errors can persist, and some of these errors can cause cancers to form. In short: TP53 (when it’s working properly) can help stop cancer from forming in elephants and in humans.
So, what’s the difference between TP53 genes in elephants and those of humans (and all other mammals that have been studied so far)? We humans have 2 copies of the TP53 gene. Elephants also have 2 copies that are similar to the human genes, but they also have a lot of backup copies called retrogenes (Asian elephants have 15-20 backup gene copies and African elephants have more than 20).
(Some of you might be curious how elephants got these backup copies. That’s a fascinating story that involves DNA, RNA, and viruses. The short and simple explanation is that some viruses (including the virus that causes AIDS) store their genetic information as RNA and in order to reproduce, the virus makes a DNA copy of its RNA and hides that copy among the DNA of the host cell it has infected. Then the host cell follows the instructions in that DNA. But, those instructions are not telling the host cell how to do its usual job. Instead, the instructions are telling the host cell to make more virus particles, which can then infect other cells. Occasionally, the viruses copy random pieces of host cell RNA (in this case, elephant TP53 RNA) that gets copied into DNA and inserted back into the elephant chromosomes. If these extra copies are not beneficial to the host animal, they may get randomly deleted over a period of many generations. But, if those extra copies are useful as a “backup file” of important genetic information, they will persist and be passed to future generations.)
The researchers’ next step was to test how effectively blood cells’ self-destruction system worked at preventing survival of cells with unfixable mutations caused by radiation or chemicals. They compared elephant cells vs. human ones and – no surprise here – with so many backup TP53 copies, the elephant cells were much better at destroying themselves if their DNA damage could not be repaired.
What it means for humans
Of course, what you really want to know is, “How does this information help us humans?” Scientists already know that a properly functioning TP53 helps to protect humans against cancer and that changes that damage this gene can cause cancer in humans. To be honest, I don’t see any immediate human application of this study, but when one looks back at the history of medical research, it’s clear that when clinicians don’t see any medical applications of fundamental biological research, they are often wrong. It’s important to recognize that although some progress against cancer comes from research that seems very practical and is expected to have short-term clinical benefit, some progress also comes from unexpected directions. Studies of other species that are done simply to understand how living things work and without any short term expectation of medical relevance often turn out to be very important in understanding cancer and other diseases of humans. For example, studies of eyelid and tooth development in mice led to drugs currently used for colon cancer, throat cancer, and several other cancer types. Studies of malformed fruit flies recently led to new drugs for a common type of skin cancer (as well as a better understanding of some human birth defects).
Although I can’t predict how or when this research will have some clinical application, I would not be at all surprised if other researchers already have some great ideas that lead to less human suffering and death from cancer (and perhaps some other diseases as well). Until then, just try to enjoy the idea that scientists have solved one more of the fascinating mysteries of the universe we live in.
Dr. Gansler is director of medical content for the American Cancer Society.
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