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Elephant Genes Could Lead to New Cancer Drug

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There's a reason Huntsman Cancer Institute says they have an "elephant doctor" and it's not because they're working on treating cancer in both elephants and humans. In fact, it's because elephants rarely get cancer. The elephant doctor himself, Dr. Joshua Schiffman, wanted to find out why. Now that he thinks he has, he wants to understand it better and find out whether that knowledge can help treat cancer in humans.

As we've already discussed, cancer occurs when cells split in two--a process which basically happens either to help an organism grow or to replace a dead cell--and errors build up in the copied DNA. Cells are splitting in your body all the time; about 579,000 to 810,000 times every second. Taking that fact to its logical conclusion would suggest that organisms which live a relatively long time or are relatively large (or even both) should have a relatively higher risk of cancer than other organisms.

In reality, that's not the case.

Dr. Schiffman--who is actually a pediatric oncologist--says, "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."

He continues, "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."

This conundrum is called Peto's Paradox. Dr. Schiffman has been working on it for years. In 2013, he published a study describing exactly how wrong those expectations were, focusing on elephants. Why they don't commonly get cancer has been a question for decades.

Elephants live between 50 and 70 years, and have approximately 100 times more cells than humans. The expectation would then be the elephants would theoretically be more at risk for cancer than humans by several orders of magnitude--some number with multiple zeroes behind it. What he found instead was that only about 4.8% of elephant deaths are related to cancer. For humans, that number ranges somewhere between 11 and 25%. The gulf between expectation and reality is shockingly wide.

Having gone that far, Schiffman decided to try to understand what was causing elephants to be so much more resistant to cancer than humans. His team found the possible answer in the elephants' DNA.

Both humans and elephants have a gene which scientists call p53. Errors in this gene are involved in more than half of all human cancers. When the gene doesn't work cells don't die as they should, split more often as they should, and collect ever more errors as they do so. These are the hallmarks of cancer. As Schiffman found, elephants have 40 copies of p53. Most humans have 2. In the case of one disease called Li-Fraumeni Syndrome, people only have 1 copy. Those individuals have over a 90% chance of dealing with cancer in their lifetime. Many get several different kinds of cancer.

His team tried practical tests. They isolated cells from the blood of both elephants and humans and subjected them to radiation, which causes breaks and other errors in DNA. Their hypothesis was that the elephants cells would repair their DNA faster and thus eliminate the possibility of developing cancer. What actually happened was that elephant cells with damaged DNA died. They were twice as likely to die as healthy human cells, and five times more likely to die than cells from patients with Li-Fraumeni Syndrome.

In some ways, this is a bit like cooking. Imagine making cookie dough and accidentally putting in far too much salt. You could try to balance out the saltiness by adding other ingredients, or you could just throw away the concoction and start over. Both methods might work, but starting over is probably the better idea.

Schiffman says, “By all logical reasoning, elephants should be developing a tremendous amount of cancer, and in fact, should be extinct by now due to such a high risk for cancer." He explains the team's hypothesis, “We think that making more p53 is nature’s way of keeping this species alive."

He's not exactly sure how it works yet, but while he works on that question Schiffman has a goal to develop a drug for humans which mimics the p53 found in elephants. After publishing his study in 2013, some people were skeptical of that goal. The National Cancer Institute's head of clinical research, Dr. Lee Helman, was one. Helman said Schiffman has "a lot of hurdles to overcome" given that scientists have "enough trouble putting human genes into human beings with all kinds of difficulty", let alone a gene from a completely different organism. Helman did say, however, that Schiffman's 2013 research supported an idea in the cancer research community that understanding how p53 works would lead to major strides in cancer treatment.

Schiffman and his team haven't been idle since then, though. With the help of Israeli researcher Avi Schroader, they've developed a synthetic form of the elephant p53. When human cancer cells in a disk are injected with it, they die.

They say they certainly haven't found the cure, but that they have high hopes for the drug they're trying to make. What they have now "is working and it's working better than we ever could have imagined."

Their goal is to have a compound ready for clinical trials in 2019.

"I'm on a quest to get rid of cancer," Schiffman said. "I think we're on the way and I think the elephants are going to lead us there."

 


Sources

Nunney, Leonard, et al. “Peto's paradox and the promise of comparative oncology.” Philosophical Transactions of the Royal Society B, vol. 370, no. 1673, 8 June 2015, rstb.royalsocietypublishing.org/content/370/1673/20140177.long. 
 
Abeggmen, Lisa M. “Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.” Journal of American Medicine, 3 Nov. 2015, www.jamanetwork.com/journals/jama/fullarticle/2456041
 
“Elephant genes hold big hopes for cancer researchers.” PBS, Public Broadcasting Service, 22 Feb. 2016, www.pbs.org/newshour/show/elephant-genes-hold-big-hopes-for-cancer-researchers.
 
“Joshua D. Schiffman, MD.” University of Utah Health, www.healthcare.utah.edu/fad/mddetail.php?physicianID=u0630147
 
Netburn, Deborah. “Why do elephants rarely get cancer?” The Washington Post, WP Company, 12 Oct. 2015, www.washingtonpost.com/national/health-science/why-do-elephants-rarely-get-cancer/2015/10/12/72a1849a-6df0-11e5-b31c-d80d62b53e28_story.html.
 
“Schiffman Lab Research.” Schiffman Lab Research - Huntsman Cancer Institute | University of Utah, www.uofuhealth.utah.edu/huntsman/labs/schiffman/.  
 
Stuckey, Alex. “Lab tests show elephant DNA may be key to fighting cancer, says Utah researcher.” The Salt Lake Tribune, www.archive.sltrib.com/article.php?id=4789317&itype=CMSID
 
“What Elephants Can Teach Us About Evading Cancer.” University of Utah Health, www.healthcare.utah.edu/the-scope/shows.php?shows=0_07bjcqt7
 
“Why elephants rarely get cancer.” Why Elephants Rarely Get Cancer - Huntsman Cancer Institute - University of Utah Health Care - Salt Lake City, Utah, Huntsman Cancer Institute, 8 Oct. 2015, www.huntsmancancer.org/newsroom/2015/10/why-elephants-rarely-get-cancer.php

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