17-20 Segment 1: Elephant DNA: The secret to cancer suppression?

RHJ 17-20A FB

 

DNA mutations happen all the time in the body, but the immune system usually detects and deals with them. When the system fails, cancer results. Yet some animals, such as elephants, almost never get cancer, and scientists have learned that the elephant DNA repair system is 20 times more powerful than the human system.

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Guests:

  • Dr. Joshua Schiffman, Professor of Pediatrics, University of Utah and investigator, Huntsman Cancer Institute
  • Dr. Vincent Lynch, Assistant Professor of Human Genetics and Organismal Biology, University of Chicago

Links for more information:

Elephant DNA and Cancer Suppression

Reed Pence: Curing cancer is the holy grail of medicine. Many researchers have spent their lives pursuing it. Many more have sought significantly better treatments. Doctors study cancer’s vulnerabilities so they can attack cancer when it happens. And they try to understand why cancer happens in the first place, so someday they can prevent it.

Dr. Joshua Schiffman: Normally cells will divide when they need to and then stop growing. In the case of cancer though what happens is the cells continue to divide over and over and over again. They’ve lost the ability to stop growing.

Pence: That’s Dr. Joshua Schiffman, professor of pediatrics at the University of Utah and an investigator at the Huntsman Cancer Institute there.

Schiffman: And eventually they become so large that they take over an organ in the body, sometimes they spread to different locations in the body and if left untreated they’ll go on to almost certainly kill the patient.

Pence: Over the course of a lifetime, about 40 percent of people will develop cancer. But what many people don’t realize is that the first steps toward cancer are happening in our bodies all the time. But they don’t get far.

Schiffman: Every day just walking down the street we’re getting hundreds of thousands, if not millions of mutations, but our body is design to actually eliminate those so that we don’t go on to develop cancer. Although even so, half of all men and a third of all women will develop cancer throughout their lifetime, and as we get older our ability to fix those mutations and the accumulation of these mutations that sneak by our DNA repair system begins to grow and if you live long enough there unfortunately is a pretty good chance that you may develop cancer.

Dr. Vincent Lynch: Cells are dying in your body all the time, so your body needs to replace those dead cells. So every time a cell dies it’s replaced more or less with another healthy cell. Sometimes that process goes awry and a so it’s not quite cancer all the way, but it’s precancerous and your body’s immune system for example, might recognize that pre-cancerous cell as not being quite right and not doing a response against it and kill it.

Pence: Dr. Vincent Lynch is assistant professor of human genetics and organismal biology and anatomy at the University of Chicago.

Lynch: Sometimes that process doesn’t happen and those cells escape for example, that immune surveillance? And then they start to mutate in ways that makes it much harder for your body to recognize them as foreign, and that allows they to escape the normal mechanisms that keep uncontrolled cell proliferation in check.

Pence: Why the immune system fails to detect those mutations is the subject of a great deal of research. As Schiffman says, age may often have something to do with it. But obviously, sometimes it doesn’t.

Schiffman: Why would children get cancer? Because this is really an interesting question, right? What would someone so young develop cancer at such an early age? They haven’t lived long enough to accumulate all those mutations that happens in time and all the environmental exposures. So, we believe that there’s a strong genetic component that contributes to the risks of childhood cancer. We’re trying to understand exactly what that component is.

Pence: Schiffman says a few children have a genetically weakened immune system. Their DNA repair mechanisms are themselves mutated. So their rate of developing cancer is very high. When cancer develops in any of us, a similar failure has occurred.

Schiffman: There are over 22,000 different genes that we have as humans and each gene has a very specific job. If those genes get altered, changed or mutated, then the instructions that those genes code no longer can be read and that gene can’t perform its job. Some of these genes, their job really is only to protect us from cancer. If you start losing those genes then you’ve lost your protection for cancer.

Pence: Lynch and Schiffman say one of the principal cancer protection genes in the body is called p53 or TP53. It’s so important that some people call it the “guardian of the genome.”

Schiffman: When a cell starts to go awry, when a cell starts to have a mutation or turn into a pre-cancer, so that there’s a spelling mistake in its DNA, p53 shows up on the scene and helps to fix it. It’s almost like a big spellchecker.

Lynch: So basically it’s hanging out in your cell all the time doing nothing. And then if your cell experiences DNA damage it does two things. It starts a stopwatch, which gives the cell time to repair the damage, so normally cells are dividing and it stops the cell from dividing until the damage is repaired. The thing is it’s counting. It’s not giving the cell an infinite amount of time to repair the damage. If it takes too long to repair the damage it causes the cell to kill itself, and so the biological rational there is if there’s only a little bit of damage the cell can probably repair that without there being much of a side effect. But if there’s a lot of damage chances are the cell isn’t going to be able to repair all of that damage very safely, so it can repair some of the damage correctly, but some of the damage may escape that repair and if that’s the case it’s better to just kill the cell.

Schiffman: But when those cancer protection genes or tumor suppressor genes, when they get mutated or they don’t work properly anymore then there’s nothing protecting us from developing cancer. The cells have lost their first line of defense.

Pence: Some animals, however, have a first line of defense that seems to never fail. For example, only about three percent of elephants ever get cancer, and Schiffman and Lynch say that flies in the face of what you’d expect of a large animal.

Schiffman: Elephants are 100 times the size of people. That means they have a hundred times as many cells, which is actually if you think about it, a hundred times as many chances for randomly developing those mutations. Not only that, elephants live quite a long time. They live 50, 60, sometimes 70 years. That many cells dividing decade after decade after decade just by chance alone all elephants should actually be dropping dead of cancer, but they almost never do.  

Lynch: There’s no relation between body size and the incidence of developing cancer. And on one level the answer is really simple – these big things have evolved ways to reduce their cancer risk. And on another level the answer is really complicated; it’s more, okay how are they doing that?      

Pence: How they’re doing that has been the subject of both Schiffman and Lynch’s research, examining the elephant genome. Their separate studies, in the journal of the American Medical Association and the journal E-Life, show that the answer is pretty clear.

Schiffman: Instead of two copies of that p53 gene we were talking about, all humans have two copies – one from their mother, one from their father, instead of two copies to protect them from cancer elephants had 40 copies. So 20 times as many copies as people.

Pence: That could create in elephants a theoretically nearly failsafe cancer surveillance system.

Lynch: One way an organism could increase its cancer resistance is just have lots of extra copies of P53p So if one of them becomes mutated and nonfunctional, there are backup redundant copies that can take over the role of the normal copy.

Pence: Lynch found extra p53 genes in skin cells of both Asian and African elephant from the San Diego Zoo. Schiffman took a similar route seeking elephant blood cells.

Schiffman: I found myself at the local Utah Hogle Zoo whenever blood was being drawn, again for other reasons we were able to get some of it to our lab and study it and sure enough what we learned was that these extra copies of P53 indeed seem to be contributing to the ability of the elephant cells to rapidly remove any type of precancerous that was occurring.

Pence: Schiffman put the elephant cells into a lab dish and exposed them to radiation and chemotherapy… prompting DNA damage to make them precancerous. And he did the same thing with human cells to compare how they worked.

Schiffman: And what we found was that always the elephant cells were much more sensitive to the DNA damage. The were able to eliminate those cells with the cancer in it much more quickly. We were able to demonstrate that the way they were doping that was they were activating this P53 system of cell death. And so the elephants we were able to say had evolved a much more robust system for eliminating cells that have DNA damage and can go on cancer. This actually makes a lot of sense if you think about it from the perspective of an elephant. They are so large, so many cells, they can’t afford to get cancer because they would go extinct.

Pence: That research is going one step further now, with the goal of turning elephant p53 into something that can help people.

Schiffman: We’re trying to figure out is there a way that we could actually somehow deliver this elephant p53 to actually give to our patients, to maybe treat or perhaps one day prevent cancer. And this is the focus of our efforts right now. And what’s the best way to get the elephant p53 into a human cancer cell in a dish and then eventually to go on and maybe in the future who knows, make a medicine that could be given to people?

Pence: The research is taking a promising turn, though the results haven’t yet been published. Schiffman’s team has exposed seven different kinds of human cancer cells to elephant p53…with dramatic results. The cancer cells shrivel and explode… killed by the elephant p53.

Schiffman: Similar to if you put human p53 into a cancer cell we’re able to actually use laboratory techniques to put the elephant p53 into it and observe the effects in some of these cancer cells and we’re able to show that some of these cancer cells in the dish are actually like you said exploding, undergoing apoptosis. They actually shrivel up and go into that death cycle and then just basically turn into little small pieces that finally disappear. So it’s really very early, but it’s still very encouraging.

Pence: But if extra p53 is so protective, Lynch asks, “Why are elephants about the only animals that have it?”

Lynch: If this was such a great answer to solving the cancer problem why haven’t all the other animals that we looked at, and we looked at maybe a hundred of them, why don’t they have extra copies of P53? If this was such an easy solution to cancer resistance they should have extra copies as well. And the fact that they don’t suggests that there might be some tradeoff that goes along with having extra copies of p53. And there are some experimental data from mouse models that suggest that as well. So people have been making mice have cancer for the last 20-30 years in order to study cancer treatments. And when you make a mouse that has extra copies of p53 there are some side effects. One of the side effects is that the males undergo reproductive senescence early infertility, so they stop reproducing earlier than normal mouse. That would seem like it would be a pretty harsh tradeoff. Evolution really cares about reproduction so it doesn’t really matter if you’re an organism that never gets cancer if you never have any offspring. So there are almost certainly tradeoffs.

Pence: Other studies that engineered extra p53 into mice show that they age quickly, at least when the p53 is turned on all the time. They didn’t get cancer, but they quickly got old in other ways. That doesn’t happen if mice are engineered so their p53 is active only in the presence of DNA damage. But genetically engineering everyone’s immune system doesn’t seem to be a likely strategy, at least not in the short run. Schiffman says the more likely route will be to try to create a medicine using elephant DNA.  

Schiffman: Can we figure out a way to take this elephant p53 and make a medicine out of it to help our patients, to help treat cancer that they have, or maybe one day in the way future to even prevent cancer just like the elephants don’t have cancer, we want to figure out a way, how can we make it so that people don’t have to get cancer again?

Pence: Schiffman is hopeful. But he’s also cautious. This is not a cure for cancer, he says, except in elephants. But it may bring us closer to one for humans, as well. You can find out more about all our guests on our website, radiohealthjournal.net.  I’m Reed Pence.

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