Huntsman Cancer Institute at the University of Utah could explain why elephants rarely get cancer. Published in the Journal of the American Medical Association (JAMA), the results may lead to new strategies for treating cancer in people. Pediatric oncologist Joshua Schiffman describes the research and tells the story of exploring how elephants evade the deadly disease.">

Oct 8, 2015 — A study led by the Huntsman Cancer Institute at the University of Utah could explain why elephants rarely get cancer. Published in the Journal of the American Medical Association (JAMA), the results may lead to new strategies for treating cancer in people. Pediatric oncologist Joshua Schiffman describes the research and tells the story of exploring how elephants evade the deadly disease.

Interview

Interviewer: Elephants rarely get cancer. A new study may explain why.

Announcer: Examining the latest research and telling you about the latest breakthroughs, The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute, University of Utah School of Medicine and Primary Children's Hospital. Dr. Schiffman, this is a great story. Before we get into it can you explain what you found?

Dr. Schiffman: Well, what we were able to show was that elephants, despite their large size, being 100 times the size of people and living for 50-60 plus years, almost rarely develop cancer. This is surprising because with so many cells dividing for so long a period of time, you would think that almost every elephant would develop cancer at a very young age. What we were able to show was that elephants may be protected from developing cancer due to extra copies of genes called p53 that protect us from cancer.

Interviewer: So might this have implications for developing new therapies?

Dr. Schiffman: We know that if we're missing working copies of these genes that there is an increased risk of cancer. In fact, we know half of all human cancers don't have p53 that works properly. The elephants on the other hand have 20 times as many p53s as people. And we think this is the reason that they don't develop cancer. Now what we're trying to do in the laboratory is figure out how do we mimic this effect of these extra copies of p53.

Interviewer: I love this idea that you're basically following nature's lead. Nature's already come up with a solution. We just have to figure out what it's done.

Dr. Schiffman: What we're trying to do in the laboratory here at the University of Utah is take a page out of nature's playbook. Just like you said, nature's already figured out. What we want to do is learn from that and see how do we apply this to children and adults who already have cancer or maybe at a genetically high risk to develop cancer.

Interviewer: One thing I was wondering is, you say that elephants really get cancer. But do we really know that? I mean, could it be that no one's been able to find it?

Dr. Schiffman: We looked at 644 recorded elephant deaths, mostly from elephants in captivity, to try to measure what is their cause of death. What we found was the cancer attributed deaths of those 644 elephants that we looked at, less than 5%. So 4.8% of these elephant deaths could possibly be due to cancer. In humans, the estimated mortality from Cancer is 11% to 25%.

Interviewer: And actually elephants aren't the only large animal that rarely gets cancer. You did an analysis of many types of animals

Dr. Schiffman: We looked at a database that the San Diego Zoo maintains. You would expect that those animals that live longer, that have more cell mass, that they would also have an increased risk for cancer. Because the more cells you have, the longer those cells are dividing, just by chance alone, the opportunity to accumulate mutations and eventually transform into cancer would be present. But what we found was that, actually, there wasn't a relationship. If anything, the larger animals like the elephants, like lions, like moose and so forth, they seem to be slightly protected from cancer.
So we think that nature has evolved to protect different species from cancer, so that they could grow large, so that they can live a long time. We believe as we expand our studies and we look further that every different animal that is protected from cancer will have evolved a slightly different way of avoiding cancer or becoming cancer resistant. This concept of evolutionary medicine of learning, what we can from nature around us is very exciting and we think holds great promise for treating our human patients.

Interviewer: So how did this even get started? I mean, it's not like laboratory scientists work with elephants every day.

Dr. Schiffman: Several years ago I was at a conference that was discussing the evolution of cancer. And one of the speakers, Carlo Maley, from the Arizona State University, was describing this phenomenon called Peto's Paradox, which is the observation that large animals like elephants develop much less cancer than you'd expect by chance alone. Carlo went on to describe that he had looked at the genome of African elephants in his laboratory and there they found that these elephants seem to have extra copies of this p53 gene.
I went up to Carlo after the talk and was discussing that in our lab at the University of Utah, we take care of patients and study patients who have something known as Li-Fraumeni syndrome, who are actually missing working copies of p53. And we said wouldn't it be wonderful to try to get elephant blood to try to compare that elephant blood from elephants that don't get cancer with patients that seem to get an awful lot of cancer, sometimes a 90-100% lifetime risk of cancer?
It was a few weeks later that I happened to be at the zoo with my children watching the elephants. Well, they went on to say that once a week at the Hogle Zoo, they draw blood from these African elephants to make sure that they're healthy and their hormones are in balance. Well, a light bulb went right off. It took several months of paperwork and scientific an ethical review from the Hogle Zoo. But since that time, I'm pleased to say that our clinical study coordinators go directly down to the whole Hogle Zoo where they receive the blood and we rush it back to the laboratory and that's where we've done our experiments.

Interviewer: What did the elephant blood show you?

Dr. Schiffman: When we look at the response of elephants cells to radiation or chemotherapy, DNA damaging agents that normally cause cancer due to mutations. We find that the elephant cells are exquisitely sensitive. It's almost like all of these elephant cells are on high alert, we think because of these extra copies of p53. When these elephant cells are exposed to these DNA damaging agents, they almost immediately undergo apoptosis, which is cell death or cell suicide. It's as if the elephants have said, "It's so important that we don't develop cancer. We need to not try to fix the cells but let's just kill them and start over from scratch."

Interviewer: How did that compare with the response from cells from people?

Dr. Schiffman: We were able to look and compare to our patients with this Li-Fraumeni syndrome and show that their cells actually don't die that frequently in response to DNA damaging agents. They continue to divide and go on with these mutations, which is what we think leads to their increased risk of cancer. But the elephant cells, much more than the Li-Fraumeni patient cells or the human controls, they, again, all went on to have this cell death or apoptosis.

Interviewer: So even healthy human cells don't go through as much self destruction or apoptosis says the elephant cells do?

Dr. Schiffman: That's right. In fact, a third to a half of all humans will develop cancer throughout their lifetime. So there is some p53 triggered apoptosis, definitely, in human cells. But it's not as good as the elephant apoptosis. The elephant apoptosis is more than twice the amount of the humans and we think that seems to be enough to protect these elephants from developing cancer.

Interviewer: Is that something you expected, I mean, that these cells would just basically get rid of themselves rather than, I don't know, try to fix the problem?

Dr. Schiffman: This was a complete surprise to us. We expected the elephant cells to just repair really quickly. But we were shocked to see that the elephant cells were repairing the DNA damage at about the same rate as the human cells. It was only when we looked at the measurement of cell death that we noticed the big difference.

Interviewer: So you know all of this is based on the fact that elephants have these extra copies of p53 - 40 of them compared to 2 in people. How they even get that many copies?

Dr. Schiffman: Yeah, that's an excellent question. When we look carefully at the sequences of these extra copies, what we discovered along with our research collaborators was that these extra copies appear to be what's called retro genes. This means that these genes have been reinserted throughout evolutionary time back into the elephant genome. So throughout the past 55 million years as the elephant developed into a large animal with a long life span, we think the reason it was able to do so was because these extra retro genes were reinserted into the elephant genome.
The other thing that we were able to show in the paper is if you take an elephant retro gene and you put it into a human cell, so we used human cell lines, we were able to actually see that there was some indication that these retro genes, these elephant genes can actually be active in a human cell and trigger some of the same responses in the same genes to be involved as we see with normal p53. This is very exciting because it opens up the door as a potential therapeutic using these elephant genes in humans.

Interviewer: And so what comes next for you?

Dr. Schiffman: What we want to be able to do is try to figure out can we actually develop a drug or approach to help these children that we care for, that other people are caring for children in hospitals all across the country and adults as well? Is there a novel way that we can discover to use this information to try to treat these cancers?

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.