How our changing DNA keeps us alive | Linda Chelico

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2:47Linda Chelico: This is TED Health, a podcast from TED, and I'm your host, Dr. Shoshana Ungerleiter. When it comes to the biggest medical questions we're still trying to answer, like why we age, why cancer develops, and how some bodies seem to resist it better than others, humans are actually just one data point. Think about it. Evolution has been running experiments for billions of years across millions of species. So it just makes sense that some of the most illuminating lessons about health and longevity can come from paying attention to the natural world around us, noticing who's thriving, and then asking how.

3:25Linda Chelico: We can learn so much from other species, and that idea is what led me to this week's What Caught My Attention segment. My initial curiosity came from an unlikely place. The genome of a whale. And not just any whale, but the bowhead whale, an animal that can live more than 200 years, grows to be larger than the size of a city bus, and somehow manages to do all of that without being overwhelmed by cancer. From a biological perspective, that combination of size and lifespan should be a disaster. More years alive usually means more time for DNA damage to accumulate. More cells means more opportunities for mutations to go wrong.

4:13Linda Chelico: And yet, bowhead whales seem to defy that math. A new paper in Nature digs into how they pull this off. And the new research stopped me in my tracks. So for a long time, scientists thought that animals that grow very large and live very long must protect themselves by being especially ruthless at the cellular level. So their bodies might quickly eliminate damaged cells before they can cause trouble. That's actually part of how elephants stay healthy, for example. But biology rarely works in clean either-or categories. And it turns out most species use a mix of strategies, balancing when to remove damaged cells and when to actually repair them.

4:57Linda Chelico: What the bowhead whale shows us is that this balance can tip in a different direction than what we've assumed, placing a much heavier emphasis on repair and long-term maintenance. There were more surprises in this study, too. When researchers put bowhead whale cells side by side with human cells, they realized that whale cells didn't need more genetic hits to turn cancerous. In fact, they needed fewer. But on paper, that should make whales more vulnerable to disease, not less. So why aren't they? Again, the answer wasn't about killing damaged cells faster. It was about fixing them, and fixing them better, even when the DNA damage is severe.

5:42Linda Chelico: Over time, that means less genetic messiness, fewer errors piling up that compound the risk of cancer, and a much more stable foundation for long-term health. In other words, the bowhead whale isn't avoiding damage. It's living in a world where cellular damage is inevitable, and responding by becoming extraordinarily good at putting things back together. At the center of this system is a protein with a surprisingly humble name, cold-inducible RNA-binding protein, or CIRBP. This protein helps stabilize broken DNA ends, recruits repair machinery, and protects genetic material while the cell does its molecular repair work.

6:26Linda Chelico: In humans, CIRBP exists, but at relatively modest levels. In bowhead whales, these proteins are produced in abundance across tissues, and especially in situations where DNA is under stress. When researchers added the whale version of this protein to human cells, the results were striking. The human samples became better at fixing their DNA and made fewer mistakes along the way. In other experiments with fruit flies, boosting CARBP helped them live longer and better withstand radiation. Together, these findings suggest that this protein plays an important role in strengthening cells and helping them recover from damage.

7:09Linda Chelico: I mean, wow. Talk about learning from other species. That said, I do want to add a caveat here. This probably isn't the whole story. This one protein alone probably doesn't explain the bowhead whale's remarkable lifespan or resistance to cancer. And other protective systems are almost certainly at work. But I'm still fascinated by the bigger idea here. With the bowhead whale, we're seeing what it looks like when evolution favors long-term care over constant cleanup. That distinction matters because for decades we've treated DNA damage as an unquestioned villain. both in humans and in other species.

7:49Linda Chelico: Damage meant danger. Mutations meant disease. The assumed solution was to quickly eliminate or repair damaged cells before they could cause harm. But this research complicates that story. In bowhead whales, damaged cells aren't automatically thrown away. Many are carefully repaired instead, allowing tissues to keep working for decades without exhausting themselves. Cells that do stop dividing still show up, but they tend to stay calmer, causing less inflammation and less disruption to the tissue around them. Aging in this framework isn't driven only by damage itself, but by how the body responds to it.

8:28Linda Chelico: And suddenly, longevity looks less like a war against imperfection and more like a long-term commitment to upkeep. As medicine and genomics rapidly evolve, that reframing feels like an important consideration. We're starting to understand the dynamic processes that shape our genes over time. And we're mapping out the constant cycle of damage, repair, and adaptation happening in every cell of your body every day. What would it look like if we thought about it in this new light? Where could medicine take us then? The bowhead whale reminds us that DNA is not a static blueprint. It's a living document.

9:08Linda Chelico: And sometimes the most powerful survival strategy isn't preventing change altogether. It's learning how to adapt to it wisely. Which brings us to today's TEDx talk. Because if whales have taught us that DNA damage isn't always the enemy, and sometimes the very processes we fear are the ones keeping us alive, this sets the stage for a deeper conversation about how we think about our own biology. As this whale research shows, the genome isn't a fixed instruction manual. It's constantly being revised. Today we have a TEDx talk from biochemist Dr. Linda Chalico, who explores a surprising twist in the story of DNA.

9:52Linda Chelico: Over the course of her career, Dr. Chalico has studied the constant tension inside our cells. Mutations that are happening all the time. Some get repaired and some don't. And here's the twist. the ones that aren't fixed aren't always a problem. In some cases, they do important work, helping us fight viruses, train our immune systems, and ultimately keep us alive. And now Dr. Linda Cielico takes the TED stage. DNA. It is sometimes called the blueprint of life. I'm sure we've all heard that before. Well, in some ways it is true. You can't change your eye color, for example, but in many ways it really isn't.

10:36Our DNA changes every day. DNA is actually getting damaged every day by external factors, like UV rays from the sun, or internal factors like chemicals. Humans do encode in their DNA proteins that can repair that damage, but those processes can't repair everything. For instance, when you go out into the sun and get exposed to UV without sunscreen, you can get a burn. That is your DNA getting so damaged that it can't be repaired. The protective effect is to let those skin cells die. However, most times your DNA repair can repair that sun damage. But my advice is don't let those proteins work too hard.

11:23Mistakes over time can be dangerous. This is best illustrated by some rare diseases where DNA repair proteins don't work properly. For one of these, a symptom is the onset of skin cancer at the age of 8 years old, nearly 50 years younger than the general U.S. population. This is part of the reason why cancer, a disease of DNA damage that does not get repaired properly, increases with age. The improperly repaired DNA damage causes mutations in the DNA. However, mutations are not all bad. Although mutations can cause cancer in some situations, in other situations they can also result in beneficial evolution.

12:12Mutations formed humans as a species and every other organism on the planet. Organisms evolve by acquiring mutations. But how does biology decide what are good and what are bad mutations? I think of it like this. When we encounter uncertainties in life, it incites an uncomfortable feeling. One that can result in an attempt to bring things back to the status quo. Repair the damage and bring things back to the way they were. However, sometimes inaction is not an option. With some uncertainties, we've just needed to weigh the risks and make the best decision with the information available. We may have had a plan, a blueprint, but at times we've had to throw that out and just wing it, induce those mutations in our life's blueprint.

13:02I think we've all been there before. I know I have, maybe too many times. I took a risk near the end of my PhD, and I flew all the way from Canada to Australia to go to a conference celebrating the 50th anniversary of the discovery of DNA. All the best people in the DNA repair field were going to be there. And I was convinced during this trip that I was going to find a postdoctoral lab to work in, in order to help me answer the question of how mutations occur in DNA, despite DNA repair proteins, and how biology is weighing these risks. Luckily, that risk worked out. And some days, I still think to myself, how?

13:44But that is another story for another time. The important part here is that I did find a professor from the United States to work with who studied exactly what I wanted to work on, and this was how bacteria deliberately introduce mutations in their DNA. He and others discovered that bacteria lacking the ability to deliberately induce mutations in their DNA grew similar to other bacteria under normal growth conditions, but under stressful growth conditions, the bacteria that could not induce mutations died first. Sticking to the blueprint was detrimental. Risk, mutation, and evolution helped the bacteria to adapt and survive in uncertain situations.

14:32So I show up to my postdoctoral lab to study this process, but instead I arrived shortly after a very surprising discovery had been made by scientists. humans and other animals were found to encode in their DNA a large family of proteins that deliberately damages and induces mutations. Now this was in addition to the process I just told you about in bacteria. Humans had evolved an additional way to induce DNA damage. So I took yet another risk and I switched my research focus to study this family of proteins and be part of figuring out the details for this exciting new discovery. And 20 years later, I'm still amazed by these proteins, but I'm sad to say that their name is not as amazing as their function.

15:19They are called Apobeck. And if I sum up Apobecks to you, I would say that these proteins are experts at winging it. They don't use a blueprint, they randomly induce mutations in DNA, and surprisingly, most of the time, it works in our best interest. Biology has pre-calculated the risks. In my postdoctoral lab, I started studying one specific Apobeck family member that helps us make better antibodies. The second time we get an infection, we have a better and faster immune response. And it's actually this Apobeck family member that's essential for initiating that process. During an infection, in real time, the DNA in your antibody-producing cells is evolving by ApoBec-induced mutations to respond to new pathogens that you're exposed to during your lifetime.

16:13Rare diseases that inactivate this special ApoBec protein results in people being immunocompromised, so inducing mutations can be an essential function. Now, as interesting and important as this process was, I wanted something more. I wanted to determine if this process could affect the whole body and not one specific part. And originally, I was trained as a microbiologist, so I wanted to get back in line with my original idea of studying DNA damage in microorganisms. And this is where I switched yet again and decided to focus my research efforts, this time back in Canada when I started my own lab here at the University of Saskatchewan.

16:59There are some viral infections that antibodies don't do a good job at clearing up. In these cases, there is another mechanism occurring from a larger part of this Apobeck family, seven different Apobeck proteins that do something more risky. These proteins cause DNA damage and induce mutations in virus genetic information in an attempt to cause mutational catastrophe and inactivate them. Now that's different than what I told you about in antibody genes, and it's another outcome of mutations. A few mutations and you have no effect, too many and you have catastrophe, and somewhere in the middle is beneficial evolution.

17:41There are many mutational paths. Mutational catastrophe happens quite easily in viruses because their genomes are very small in comparison to human genomes. But there's also a risk for evolution. If Apobex don't cause mutational catastrophe, the lesser number of mutations may cause the virus to evolve. My lab has discovered that these proteins work together to prevent this from being a frequent occurrence. However, they are winging it, so things may still go wrong. This is why a burning question for me and others in the field was how these Apobex that cause mutations in virus genetic information avoid human DNA.

18:23Sometimes the virus DNA is right beside the human DNA in our cells. As research progressed, it became clear that sometimes apobacs do induce mutations in our genome. The extent to which this occurred was realized from precision medicine. Precision medicine involves the sequencing of a person's DNA to find a personalized treatment for many conditions, but especially cancer. Decades of collecting this sequencing information from tumors uncovered that ApoBEC-induced mutations are found in approximately 75 % of cancer types. Myself and others jumped in the field to find out what this meant. This is because the mutations themselves don't tell us the function of the mutations.

19:13Were they causing cancer cell catastrophe, killing the cancer cells like viruses? or were they causing cancer cell evolution, creating new functions like the antibody genes? The problem answering this question is that if Apobex caused cancer cell catastrophe, killing the cancer cells, this will never be detected in the clinic. Only the evolution events that resulted in someone developing cancer is recognized when someone goes in the clinic and is diagnosed. How many times did Apobex take the path of having the cancer cell evolve versus helping the cancer cell to die? To answer that, my research group followed in the lab the fate of Apobex-induced DNA damage from the beginning.

20:00The results showed multiple paths depending on the conditions that we exposed the cells to. Sometimes Apobex did cause the catastrophe and killed the cancer cells, and sometimes they help the cancer to evolve. Right now, we are determining the probability of going down each of these paths under different conditions. By knowing the path after ApoBEC-induced damage, we can develop new treatments for cancer based on managing ApoBEC activity. We can transform cancer treatment into one that can direct the tumor to go down a certain path rather than chasing what the tumor is doing. Studying Apobex gave researchers the blueprint of cancer.

20:48As the goal to understand the source of mutations in cancer began to focus more on the role of Apobex in cancer, mutations began to be considered from many different perspectives. Detrimental DNA damage, evolution, disease, immune responses. Mutations affect so many aspects of biology, life, our world, good or bad. These discoveries have helped us to understand that DNA changes every day and over our lifetime. Personally, Apobex have taught me to embrace change in my everyday life. Several times I had to just wing it to keep following our data, and it led to several new discoveries. Not following the blueprint was uncomfortable at times, but I've learned to do it.

21:37And perhaps we all should. It's in our DNA. Thank you.

21:52Linda Chelico: That was Dr. Linda Chelico at TEDx University of Saskatchewan in 2024. And that's our show for today. Thank you so much for listening. TED Health is a podcast from TED, and I'd love to hear your thoughts about this episode. Send me a message on Instagram at ShoshanaMD. This episode was produced by me, Shoshana Ungerleiter, and Jess Shane. Edited by Alejandra Salazar and fact-checked by Vanessa Garcia-Woodworth. Special thanks to Maria Lages, Farrah Degrange, Daniela Balarezo, Constanza Gallardo, Tansika Sangmarniwang, and Roxanne Highlash.

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