Ep 203 Cancer Part 2: Why does it happen?

Each of our cells can become cancerous. It’s an uncomfortable, yet unavoidable truth. Nor is it a truth restricted to our species - cancer is a consequence of complex life. The features that make a cell cancerous are those that, under other circumstances, are beneficial, essential even, for an individual’s growth and survival. How is that possible? In the second installment in our series, we’re putting cancer under the microscope to consider the qualities that underlie a cancer cell’s success in our body. By placing cancer in an evolutionary framework, we can not only understand why cancer is so darn prevalent, but we can also leverage that knowledge to devise new approaches to treatment - working with evolution rather than against it. If you’ve ever wondered why we haven’t come up with a cure for all cancer or why some animals get cancer more than others, this is the episode for you. Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

• 0:01Speaker 00

  This is exactly right.

• 0:06Speaker 01

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• 1:03Speaker 02

  Hey, I'm Niall Rogers. This fall, I'll be driving across the country, meeting some of today's coolest and most fascinating artists. We'll explore the stories before the moments that changed everything. Because every musician remembers the moment where it all began. Experience Before the Moment, a Lincoln original series on the iHeartRadio app, YouTube, or wherever you get your podcasts.

• 1:35Speaker 03

  Throughout this series, we'll be discussing many aspects of cancer diagnosis and treatment, and we will be sharing several personal stories related to cancer. Some listeners might find this content upsetting. Please listen with discretion.

• 1:49Speaker 04

  In the fall of 2024, I had just sent my oldest off to start his freshman year of college, and my youngest was starting high school. We had a very busy summer, and I was trying to settle into our new normal. I'd started to gain weight earlier in the year, and even more recently, had started becoming very fatigued. When I talked to my gynecologist about it at my checkup, we discussed that I was probably beginning perimenopause. Most of my symptoms seemed to line up. However, in late September, on a Sunday afternoon, I got a horrible stomach ache after eating lunch. The stomach ache persisted off and on for a few days, and I thought maybe I'd had food poisoning. It eventually got somewhat better, but I was still sore and even made the comment to my coworkers that I felt like I had done a million crunches.

• 2:32Speaker 04

  I started to have cramping again one week later, again on a Sunday, but this time I was also having chills and nausea. So I went to an urgent care clinic where they did an x-ray and said that I was constipated. However, they wanted me to follow up with my PCP the next morning. I was unable to see my PCP, but I did see an on-call provider, and she sent me for a CT scan. Thankfully, I was able to get it done that day. On my way home from the CT scan, the on-call provider called me and told me to turn around and go to the emergency room as soon as possible. Her exact words were, "Your skin looks rough." I was septic and had emergency surgery the next day for a perforated bowel, and they also removed a suspicious part of my colon. It came back as stage-two colon cancer.

• 3:16Speaker 04

  Genetic testing revealed that I had Lynch syndrome, which is a genetic condition that increases one's odds for GI, colorectal, ovarian, uterine, and other types of cancers. I also tested positive for POT1 tumor predisposition syndrome. Because of these markers, and the fact that my grandmother passed from ovarian cancer, I chose to have a complete hysterectomy, including ovaries. I also have to have yearly colonoscopies and EGDs and other monitoring that needs to be done, including skin checks every six months, regular CT scans, and lab work. I feel very thankful to be NED or no evidence of disease at just shy fifteen months, but I've made it my mission to inform and encourage my friends and family members to get their colonoscopy.

• 4:01Speaker 04

  I was forty-five at the time of diagnosis and was able to start my screening that year, but I kept putting it off because I was too busy, and if I'm completely honest, I didn't think anything like this would happen to me. I considered myself relatively healthy, I ate right, I exercised, but my genetics had other ideas.

• 4:20Speaker 05

  We began in the fall of 2024 with the weirdest diagnosis I could have never imagined for myself. And I've imagined tons of diagnoses. I'm a nurse and a Virgo and an oldest child who grew up in the 80s and 90s who copes by catastrophizing. So, trust me, I've diagnosed myself with plenty of things over the years, but not metastatic breast cancer. Of all the things, that was not on my lifetime bingo card. Among the many things that breast cancer has forced me to change, it was that I have to be okay with vulnerability and frailty. I've never been comfortable with those things before. My body has really been through the wringer this past year, from surgery to chemo to radiation, now oral chemo.

• 5:01Speaker 05

  It has been poked, prodded, scanned, chopped up, stabbed, poisoned, and irradiated. I should have known what was in store for us when I was getting my implanted chemo port, and they had to tape my breasts to the side rail so that it wouldn't move and mess up the procedure. That was just the beginning. I have literally lost track of the number of people who have seen my breasts, the number of imaging procedures or scans I've had done. I've never felt worse in my life than I have this past year, and I went to nursing school. There have been times I wanted to die, just to let the cancer take me. My body betrayed me, and not just by trying to kill me. It also made it so I had no control over things

• 5:43Speaker 05

  like my bowel or my bladder. I crapped in my pants when I thought it was just gas, or like that time when I peed on the sidewalk while walking my dogs, super fun. Even now, my chemo brain is legit, and I don't remember what it's like to not be nauseated. I've had to learn that I don't have to put a brave face on. I can be vulnerable. I can ask for help, and I can share, when my instinct really has always been to protect others from the ugliness that I've been facing. It doesn't diminish who I am as a caregiver. It really is okay to prioritize myself and my needs, that I can take time to listen to my body, and I can pause and I can rest. I have literally been fighting for my life, and it's okay to take a day off.

• 6:27Speaker 05

  Thanks, cancer, for these epic life lessons. I'm better at advocating for myself now and listening to my body and its needs. It is okay to give myself grace. I do have to say, though, I would give breast cancer zero stars. I do not recommend it.

• 7:28Speaker 03

  Thank you, everyone, who has shared your story with us. And also, just a big thank you to everyone who wrote in to share your story. It is every time I just pinch myself and I'm so grateful that so many of you are willing to share these vulnerable experiences. And because this is really is like these firsthand accounts are the backbone of this of this podcast. They bring so much that we couldn't that we could not.

• 7:53Speaker 00

  Yeah, they absolutely do. This podcast would not be the same without your firsthand account. So thank you so much. And we have a lot more that we'll be sharing with you throughout this episode and throughout the series as well. So thank you again to everyone who submitted your firsthand account. We really wish that we could have included every single story that we had the privilege to hear. So thank you. It means a lot to us.

• 8:12Speaker 03

  It does. Hi, I'm Erin Welsh.

• 8:15Speaker 00

  And I'm Erin Omenupdike.

• 8:17Speaker 03

  And this is This Podcast Will Kill You.

• 8:19Speaker 00

  Welcome to episode two.

• 8:20Speaker 01

  Two of our series on cancer.

• 8:23Speaker 03

  It's a big one.

• 8:24Speaker 01

  It really is.

• 8:25Speaker 03

  Uh, Sphira, if this is your first time tuning in to this series, go check out the first episode.

• 8:31Speaker 01

  Yeah.

• 8:31Speaker 03

  We've got four total, Common For Ya. And, um, and each of these episodes covers a different aspect of cancer. And really, our intent with this is just to lay the foundations of knowledge so that in the future, we'll be able to then you'll be able to like, oh yeah, I know what cancer is. Because in this episode on lung cancer, because I listened to the cancer series.

• 8:53Speaker 01

  Exactly, exactly, exactly.

• 8:54Speaker 03

  It gives us an opportunity to explore the big picture of what this all means.

• 8:58Speaker 01

  Right.

• 8:58Speaker 03

  What does that mean? How are these episodes organized? Great question.

• 9:01Speaker 01

  We'd love to tell you.

• 9:02Speaker 03

  If you didn't listen last week, last week, we really explored the concept of cancer from both like a biological perspective, well, more clinical perspective, as well as like through history, how that has changed and our current conception of it. In this episode, we're going to be going over the evolutionary aspects of cancer, the cellular aspects of cancer, like why is cancer so prevalent?

• 9:24Speaker 01

  Right.

• 9:25Speaker 03

  Next episode, treatment. Last episode, yeah. I mean, that encompasses a lot.

• 9:31Speaker 01

  Yeah.

• 9:31Speaker 03

  And the last episode, the fourth and final, is all about, um, screening, prevention, kind of understanding the landscape of cancer today and where we might go from here.

• 9:40Speaker 01

  Exactly, exactly.

• 9:41Speaker 03

  Yeah.

• 9:41Speaker 01

  And that's all quite a lot of ground to cover, but there's a lot that is going to be unexplored. And like you said, Erin, this is really the jumping off point. These are not the only cancer episodes that we are ever going to do. We have lots of plans to cover so many individual types of cancers. And we also have a massive list of sources. If anyone gets inspired and wants to learn more about cancer from a big picture perspective or individual cancers, my goodness, do we have sources for you.

• 10:12Speaker 03

  So many opportunities to do that.

• 10:13Speaker 01

  So.

• 10:13Speaker 03

  Yeah, yeah. Uh, and as you'll hear, no two cancers or experiences with cancer are exactly alike. And so again, we are just so grateful to the providers of our firsthand accounts to really just showed us like a sample of what it means to have cancer, to be diagnosed with cancer, to be going through treatment, to lose someone to cancer, to be a caregiver, just so many different facets of this experience.

• 10:36Speaker 01

  It affects so much.

• 10:37Speaker 03

  Yeah, that, you know, we're in these episodes, we're really talking about the biology of like, we're talking about from a biological and historical perspectives. We're not talking about these experiences. And so that is where these firsthand accounts have been so integral. So, thank you again.

• 10:53Speaker 01

  Thank you. Thank you. They really do mean everything to us.

• 10:55Speaker 03

  Yeah. Okay. One more piece of business.

• 10:59Speaker 01

  Last piece of business.

• 11:00Speaker 03

  Quarantiny time. We're still doing it.

• 11:02Speaker 01

  We're still doing it. If you didn't hear last week, we are no longer doing alcohol in our quarantine recipes. So you could consider them all placebo ritas, but we're gonna call them quarantinis.

• 11:11Speaker 03

  Whatever strikes us.

• 11:13Speaker 01

  And this week, we're drinking.

• 11:15Speaker 03

  The crab.

• 11:16Speaker 01

  The crab.

• 11:17Speaker 03

  It's an affogato.

• 11:18Speaker 01

  Espresso, ice cream. Let's go get one after this.

• 11:21Speaker 03

  Subscribe to our socials to, yeah, let's go get one. Subscribe to our socials to see how it's made. And check out our website where you can find all the other sorts of TPWKY related things.

• 11:36Speaker 01

  ThisPodcastWillKillYou.com.

• 11:37Speaker 03

  Yeah, check it out.

• 11:38Speaker 01

  Rate, review, and subscribe. We're also on YouTube.

• 11:40Speaker 03

  And now for the real stuff.

• 11:44Speaker 01

  The real stuff. Okay. Let us get in to the biology of cancer, shall we?

• 11:49Speaker 03

  We shall, after this short break.

• 11:53Speaker 01

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• 12:26Speaker 02

  Hey, it's Niall Rogers, host of Before the Moment, a Lincoln original series. I'm driving across the country, meeting some of today's most fascinating artists. We're exploring the stories before the moment that changed everything. This week, I'm joined by rising star Sienna Spiro.

• 12:45Speaker 06

  I love the sixties. I feel really jealous. That I I wasn't alive for it. I'd be interested like knowing what that was like and seeing the way culture and art has has progressed today. How do you find it?

• 12:55Speaker 02

  Wait a minute, I'm

• 12:56Speaker 06

  I'm sorry, I have so many questions. Sorry.

• 12:58Speaker 02

  You're not nervous, are you?

• 12:59Speaker 06

  I am nervous.

• 13:00Speaker 02

  You are?

• 13:01Speaker 06

  I am. I feel like insecure about my experience. I know I shouldn't, but you know, I'm twenty. I haven't really lived my life yet. And then sitting in front of somebody that has lived an enormous life is is intimidating. And sometimes I feel like talking about myself is just not as interesting. So that's why I feel a bit nervous. I'll try and I'll try and ignore it.

• 13:20Speaker 02

  Please do. Experience Before the Moment, a Lincoln original series on the iHeartRadio app, YouTube, or wherever you get your podcasts.

• 13:46Speaker 07

  On August twenty eighth, twenty twenty five, I got a call from my dermatologist. He told me a biopsy on what I thought were hives had come back as malt lymphoma and asked me to come into his office so we could talk. What followed were months of emotional whiplash. At first, I didn't understand the diagnosis. Then came long stretches of waiting, waiting to learn what my next steps were, waiting for answers, and finally getting information without a clear plan. Eventually, a treatment plan came together, but the uncertainty leading up to it was one of the hardest parts. Malt lymphoma stands for mucosa-associated lymphoid tissue lymphoma. It's a slow-growing form of non-Hodgkin's lymphoma, and in my case, it appeared in my skin. I was told there are a few possible causes, including infections and genetics.

• 14:30Speaker 07

  But for me, the most likely explanation was simply bad luck. This type of lymphoma is considered rare and is more commonly found in men in their fifties and sixties. I was thirty one, active, teaching and competing in country dance, and otherwise healthy, which made the diagnosis feel especially surreal. After consulting both my local oncologist and an oncologist at the Mayo Clinic, my husband and I decided on localized immunotherapy rather than surgery and radiation. I traveled to the Mayo Clinic in Scottsdale, Arizona for treatment with rutuximib, which involved injecting the medication directly into the tumors. At the time, I had nine tumors across my arms. The process involved numbing injections followed by the drug itself, totaling about twenty to thirty injections per session.

• 15:16Speaker 07

  I have a high pain tolerance, but right after treatment, my body started shaking and I felt extremely cold. It lasted about five minutes and then I was fine, but it was still unsettling. I remember looking at my husband and saying I wasn't sure I could do it again. I did. After three sessions, the tumors began to shrink. Six weeks after my last treatment, they have almost completely disappeared. Now I continue regular monitoring. Any new bumps are considered a recurrence and something I may live with long term. While I'm grateful for an overall favorable prognosis, the experience permanently changed how I think about my health and my relationship with my body.

• 15:56Speaker 00

  When I was thirty-two in twenty sixteen, I was diagnosed with breast cancer. I found a lump in the shower, went to my local doctor, and within ten days I had been diagnosed. What followed was just a whirlwind. I had a right-sided mastectomy and full node clearance. I had an immediate D E P reconstruction where they took the fat from my stomach and made a new breast out of it. I had egg retrieval because we hadn't had children. And then I had six rounds of chemotherapy and radiation for three weeks. In twenty twenty-five, nine years later, I'd had a sore hip and it was starting to affect my day-to-day life, so I went to the doctor.

• 16:41Speaker 00

  I saw the physio, who wasn't worried about it, went home, went on a trip where it felt like something had moved and I assumed I'd slipped a disc. So I came back, went to the physio again, a female physio this time, and she referred me immediately. When I saw the physio at the hospital, again, he wasn't too worried. I didn't have any massive red flags, but he sent me for an MRI just to make sure because I had a history of cancer. And at the end of March, I got a phone call to say that unfortunately, I had several deposits in my spine and in both hips. And it looked like secondary breast cancer. I had to have a bone biopsy while I was awake, which I do not recommend.

• 17:26Speaker 00

  Um, and I found out that, yeah, it definitely was cancer and I would have to be treated. At this point, I had no idea what that meant. I didn't know if it had spread. I didn't know if I had weeks or days or months left to live. And it just, it just absolutely, it was horrendous. That was nine months ago. I am medicated. I'm on a treatment called ribociclib, which is a tablet. So I take it almost every day. It's really non-invasive and I'm now at the point where I only have to go into the hospital every two or three months. I hope that I continue to improve or stay stable, which is what my last couple of scans have showed.

• 18:12Speaker 00

  I know some people have been on this drug for eight to 10 years and are just still going. So I really hope that I continue to live and thrive like I am doing now for a long time to come.

• 18:49Speaker 03

  So I actually want to start this week's episode exactly where I started last week's episode, not where I ended it.

• 18:57Speaker 00

  Okay.

• 18:57Speaker 03

  But where I started it, which is.

• 18:59Speaker 04

  With the definition of cancer.

• 19:00Speaker 03

  Okay.

• 19:00Speaker 04

  Which is a logical place to start.

• 19:02Speaker 03

  Yeah, yeah, yeah. Yeah, sure.

• 19:03Speaker 04

  So I'll go back to that National Cancer Institute definition.

• 19:06Speaker 03

  Great.

• 19:06Speaker 04

  Quote, "Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body." So what does that really mean? If you've ever built a Lego kit, you've built a Lego kit at some point in your life.

• 19:23Speaker 03

  I've built Legos. But I don't know if I ever had a kit.

• 19:27Speaker 04

  Okay, so if you have ever built, if anyone listening and watching has built a Lego kit, you could imagine that it comes with a set of instructions. Like, if you want to build a rocket ship that really looks like a rocket ship, you're gonna need to follow the specific instructions that come in that Lego box.

• 19:41Speaker 03

  I mean, I've built many IKEA pieces of furniture. Is that the same kind of thing?

• 19:44Speaker 04

  Very similar.

• 19:45Speaker 03

  Okay, great, great, great.

• 19:46Speaker 04

  Very similar idea, just more pieces, etc.

• 19:48Speaker 03

  Perfect.

• 19:49Speaker 04

  But in the box, there are also a lot of different kinds of pieces of Legos or IKEA bits, right? Some of them all look the same. There's like 15 different dowels. There's like 24 different 4x4 squares or whatever.

• 20:02Speaker 03

  Oh, my gosh, yeah.

• 20:03Speaker 04

  And some of them look a little bit different from each other. And in order to build the thing you are trying to build, you have to follow those instructions really explicitly.

• 20:14Speaker 03

  I kind of, I have to admit, I love putting together IKEA furniture.

• 20:18Speaker 04

  You would love a Lego kit, then.

• 20:20Speaker 03

  I'm sure that I would.

• 20:22Speaker 04

  Our bodies are kind of the same. We have to function as one entire organism, a rocket ship, an IKEA piece of furniture, if you will. But we are made up of trillions of individual cells. And we started out as just one cell, which is a little bit different than IKEA furniture, because our cell had to divide and divide a bunch of times. But this process of cell division is extremely tightly regulated.

• 20:52Speaker 03

  Oh, yeah.

• 20:52Speaker 04

  Because if every cell in our body just divided nonstop, it would be madness.

• 20:58Speaker 03

  It would be a problem.

• 20:59Speaker 04

  Would be, we wouldn't be here, in short.

• 21:02Speaker 03

  Yeah.

• 21:02Speaker 04

  So we have sets of instructions that are encoded into our DNA.

• 21:07Speaker 01

  Which have patterns, instructions that our cells are going to use to make the right types of tissue in the right types of places.

• 21:17Speaker 03

  Mm hmm.

• 21:18Speaker 01

  To grow and to replicate when it's appropriate to grow and replicate and to not like build a castle on top of your rocket ship out of all of your Lego bricks, right?

• 21:27Speaker 03

  Right. It's like instructions on instructions on instructions.

• 21:31Speaker 01

  Exactly.

• 21:31Speaker 03

  You will grow and replicate, but not only that, you're going to become this specific type of cell.

• 21:36Speaker 01

  This specific type of cell.

• 21:36Speaker 03

  And this specific type of organ in this specific little bit.

• 21:39Speaker 01

  And then you're going to forget how to do all those other things that you used to be able to do.

• 21:43Speaker 03

  Yeah.

• 21:43Speaker 01

  We'll get there. So our cells determine when and how to divide based on a lot of different sets of instructions. And there is redundancy built into this process, and that is to protect against the inevitable mistakes that occur in the process of cell replication.

• 22:00Speaker 03

  Mm hmm.

• 22:00Speaker 01

  So we have a lot of checkpoints in what is called our cell's cycle and how our cells divide. Our cells rely on signals and communication with other cells. And like you mentioned, cells also differentiate. So they specialize into different types of cells in order to organize into tissues and organs, and then they only do that one certain thing. Your heart cell is just heart selling. It's not out here trying to be a skin cell anymore.

• 22:26Speaker 03

  No, no, no.

• 22:26Speaker 01

  Even though they came from the same place.

• 22:28Speaker 03

  Right.

• 22:28Speaker 01

  Okay. So cancer cells kind of take all of the pieces out of a Lego box, throw out the instruction manual, ignore any guidance on what these rules of building are supposed to be.

• 22:43Speaker 03

  Mm hmm.

• 22:44Speaker 01

  So to really understand how this is happening, we can look through some of the rules of cell growth in detail and see how cancer cells are just breaking every single one of them. And, and I know you're going to get into this a little bit more, Erin, they also leverage these rules.

• 23:01Speaker 03

  Yeah, they do.

• 23:02Speaker 01

  In a way that benefits them and not us.

• 23:04Speaker 03

  Mm hmm.

• 23:05Speaker 01

  So.

• 23:06Speaker 03

  I'm excited about that.

• 23:10Speaker 01

  So one of the rules that our cells typically follow is that they only grow and divide in the presence of what are called growth factors or growth signals, meaning that they're waiting for signals from cells and around them to determine if it is actually the right time to divide.

• 23:26Speaker 03

  Right.

• 23:27Speaker 01

  Cancer cells either ignore these signals entirely, or they just make their own. They just make their own growth signal and then they're like, hey, we're Telling you to grow, keep growing. So what we see, and you talked about this in last week's episode, Erin, in a lot of cancers are what are called oncogene mutations. And this means changes in certain genes that are involved in turning on growth, replication, and development signals all the time, which allows for this continuous cell division and growth of these masses of cells. So we see mutations in oncogenes in a lot of cancers. Almost all cancers have at least some oncogene mutations.

• 24:07Speaker 01

  And there are a few that are quite prevalent, like a few big ones that are prevalent in nearly all cancers. So you might have heard of some of these when you're looking up cancer things. Some of these are like RAS or RAS. And there's a bunch of different versions of RAS. And these are things that basically, when they are switched on, they just allow for cells to continue to grow uncontrollably. And they're switched on in a lot of cancers.

• 24:34Speaker 03

  Gas pedal to the floor.

• 24:35Speaker 01

  Gas pedal to the floor. Another mechanism that you also talked about a little bit last week's episode is that all of our cells typically have the ability to turn off cell division if they need to turn it off entirely. And they're able to recognize if our cells and the DNA within our cells gets damaged. So that they can stop that process of cell division if there's damaged cells or damaged DNA and not replicate that damaged DNA.

• 25:05Speaker 03

  Yep.

• 25:06Speaker 01

  One of the ways that we do this in our cells typically is through a process called apoptosis, which is programmed cell death. And it basically is that our cells are recognizing damage and they're saying, this cell, you need to die. This cell, you need to die.

• 25:20Speaker 03

  Right. Stop, done.

• 25:21Speaker 01

  Exactly. And then our immune system comes in and they do the thing. They do the job. Cancer cells, you can guess, turn these mechanisms off. And a lot of the genes involved in this process, we call tumor suppressor genes.

• 25:34Speaker 03

  Right.

• 25:35Speaker 01

  And in cancer, these mechanisms are turned off.

• 25:39Speaker 03

  Yep.

• 25:39Speaker 01

  That's the, take out the brake of the car.

• 25:42Speaker 03

  The brake is broken.

• 25:43Speaker 01

  It's completely gone.

• 25:44Speaker 03

  Yeah.

• 25:44Speaker 01

  And there are a lot of different kinds of tumor suppressor genes, but I'm going to give everyone a concrete example because then I think we'll be able to connect it back.

• 25:51Speaker 03

  Yeah.

• 25:52Speaker 01

  It's BRCA.

• 25:53Speaker 03

  Oh, okay.

• 25:53Speaker 01

  Okay.

• 25:54Speaker 03

  Okay.

• 25:54Speaker 01

  You gave me a face like it was going to be something different.

• 25:56Speaker 03

  I don't know.

• 25:56Speaker 01

  It will be something different, the face that you're making.

• 25:58Speaker 03

  Yes, yes, yes.

• 25:59Speaker 01

  Yeah. But BRCA1 and BRCA2, I think most of us has probably heard of. These are the genetic mutations that are associated with a significantly increased risk of breast cancer, ovarian cancer, but also melanomas, pancreatic cancer, lots of different types of cancers. And these are tumor suppressor genes. So if somebody is born with a certain version of these genes, the certain copy of BRCA1 or BRCA2, then they are not making a protein. And in this case, the protein is supposed to help identify and repair broken DNA. So if you can't do this, if you can't identify and repair broken DNA, then your cells have a tendency to accumulate more mutations and that leads to this increased risk of cancer.

• 26:42Speaker 01

  But there is another classic tumor suppressor that I feel obligated to talk about because it is, its function is affected in almost every case of cancer. And that is TP53.

• 26:55Speaker 03

  That's what I thought you were going to talk about.

• 26:56Speaker 01

  Yeah, that's what I figured.

• 26:57Speaker 03

  What, what proportion of cancers?

• 26:59Speaker 01

  Well, okay, 50% of cancers have a mutation in this specific gene, TP53.

• 27:06Speaker 03

  Yes.

• 27:06Speaker 01

  But almost all cancers, over 90%, have some kind of malfunction of the function of this P53 protein. So this TP53 gene encodes for a bunch of different versions of this specific protein that does so many different things in our cell cycle. It activates DNA repair proteins, it halts the cell cycle if there is damage to DNA, it initiates apoptosis, it's involved in a process called senescence, which is very important in cancer biology and is like when our cells age. To a point where our body decides, stop replicating forever.

• 27:43Speaker 03

  Right. You're too hard to keep an eye on.

• 27:45Speaker 01

  Exactly.

• 27:45Speaker 03

  It's enough.

• 27:46Speaker 01

  You're unreliable at this point. I'm taking away the keys. You know? And we see mutations in this particular gene, like I said, in half of all human cancers and disruption of the function. So even if the gene is still making the protein.

• 27:58Speaker 03

  Somewhere.

• 27:58Speaker 01

  Something else. The protein can't do its job anymore. So this particular gene is really important in cancer formation.

• 28:06Speaker 03

  It's a big deal.

• 28:07Speaker 01

  It's a really big deal. There's a condition where people could be born with a non-functional copy of this gene. And that results in a condition called Leiframani syndrome.

• 28:15Speaker 03

  Next week's book, book club episode.

• 28:17Speaker 01

  Oh, amazing.

• 28:18Speaker 03

  Yes.

• 28:18Speaker 01

  Oh, so definitely listen to that one. And that you are prone to a wide variety of cancers with Leiframani syndrome. And usually quite early in life compared to when we typically see cancers. But there's more. There's more that cancer cells do. Cancer cells also, they start to up-regulate. So like encourage this process that keeps them alive indefinitely. So most of our other cells can only divide a certain number of times. And then at a certain point, they start making mistakes that are completely deleterious to the cell. So then they just can't do it. Cancer cells have enzymes that they make to keep our DNA viable to continue replicating forever.

• 29:01Speaker 03

  Right. Override, override, override.

• 29:03Speaker 01

  Override, switch, override, switch. We also see that cancer cells alter how they do metabolism.

• 29:10Speaker 03

  Yeah, they do.

• 29:10Speaker 01

  They alter how they do metabolism in ways that allow them to survive better. For example, they can survive better in low oxygen environments. They can adapt to whatever nutrients are available in the environment. And speaking of oxygen, because oxygen is really important for all of our cells to be able to grow. And the way that our cells get oxygen in our bodies is through our bloodstream.

• 29:33Speaker 03

  Of course.

• 29:34Speaker 01

  And to get blood, you need blood vessels because that's where our blood happens to be contained. So cancerous tumors up-regulate the process of angiogenesis, which is the formation of blood vessels. So they make their own blood vessels in order to feed themselves.

• 29:50Speaker 03

  Yep.

• 29:51Speaker 01

  We also see changes, like modifications of the genome that aren't just mutations, other ways that they change the genome without having to have an actual DNA mutation in there. We see that they can also, we said how cells have to differentiate and become like only a heart cell.

• 30:09Speaker 03

  Yeah.

• 30:10Speaker 01

  Cancer cells can undo that differentiation to make cells look more like stem cells, which divide indefinitely and can do any sorts of function, etc.

• 30:21Speaker 03

  Yeah, we can do whatever, take whatever form.

• 30:23Speaker 01

  Right, exactly. So that's like on the tiniest little micro level, all of our cells are doing this really weird and wacky stuff. On the slightly more macro level, looking a little bit bigger at like the cancers and their environment, if we will.

• 30:39Speaker 03

  The ecology of a tumor.

• 30:40Speaker 01

  Ecology of a tumor. They have really big impacts on things like our inflammatory system.

• 30:46Speaker 03

  Yeah.

• 30:47Speaker 01

  And what's so interesting is that cancers activate our inflammatory system. They activate our immune system and pathways across basically all cancers. And yet, they also are incredibly good at avoiding our immune system's destructive processes.

• 31:07Speaker 03

  Yeah.

• 31:08Speaker 01

  So they are using the parts that benefit them, like because inflammation brings oxygen, it brings blood, it brings other cells and things like that. But then they are still evading the destructive process, our immune system, that would normally get rid of them. And of course, like I mentioned last week, one of the biggest things that cancerous tumors do, or that cancer cells do in general, is that they are traveling.

• 31:33Speaker 03

  Yes.

• 31:34Speaker 01

  They are traveling widely throughout our body. Individual cells, clumps of cells are breaking off and they are traveling throughout our body, which can then cause additional disease in distant areas. So cancer cells do a lot. And a lot of these changes are due to mutations in our DNA that are allowing for some of this evasion of typical checkpoints, like the continued replication and things like that. But we also can see a lot of these types of mutations in people that will never develop cancer. And in a lot of our so-called normal cells, like the same mutations can be present, but there's no cancer there. And that is why cancer is not just a genetic disease.

• 32:17Speaker 01

  It's a disease of what we call G by E, or genetic and environmental interactions.

• 32:24Speaker 03

  Right.

• 32:25Speaker 01

  So the mutations that we know are associated with cancer are a necessary, but not sufficient part of cancer biology.

• 32:34Speaker 03

  Right. A cancerous cell doesn't turn cancer simply because it has one mutation.

• 32:38Speaker 01

  Exactly, exactly. These mutations can arise spontaneously. We might be born with some of them, but they also could arise from exposures to things that are actually mutagens. And that might be like tobacco smoke, which has so many different carcinogens in it that do in fact cause damage to our DNA and can result in some of these deleterious changes. Or like a virus, like you talked about last week, inserting some of these oncogenes into our DNA. But there also has to be something that stimulates these type of mutations to actually persist and take over. So we now know, and we don't fully understand this all, Erin, but that some of, especially

• 33:22Speaker 01

  the environmental exposures, might contribute in more ways than just affecting our DNA. Right? So like, yes, tobacco smoke is going to damage your DNA and inhibit DNA repair and increase your mutation burden. But a lot of exposures also are going to potentially just create an environment in our cells and in our tissue, whether that's increase in inflammation.

• 33:47Speaker 03

  Right.

• 33:48Speaker 01

  Whether that's, whatever it is, that we don't fully understand, this like tumor microenvironment effect, but we know that it's an essential part of this cancer formation process. And that's where we think that a lot of these environmental exposures, that we don't fully understand the direct links.

• 34:04Speaker 01

  How those might be playing a role.

• 34:05Speaker 03

  Like mechanistically. It's not just about the genetic changes. It's also about these other things that allow for that cell to evade immune detection or to get nutrients or whatever.

• 34:17Speaker 01

  Exactly.

• 34:18Speaker 03

  Like all these different factors.

• 34:18Speaker 01

  Exactly. And I feel like what this really underscores is how much of a kind of perfect storm of events has to happen for cancers to be able to develop. And it also helps us know why aging is such an important risk factor. Because the more that your cells divide, the more likely any of these mutations might take place. But you really do have to have the right sets of mutations in the right cells, in the right environment, with the right supporting cell cast at the right time for these cancer cells to be able to take hold and eventually take over.

• 34:56Speaker 03

  It is, it's a perfect storm, but it's storming all the time.

• 34:59Speaker 01

  It's storming all the time. Right. And while all cancers break all of these different rules that I went over, every single one does it in slightly different ways.

• 35:11Speaker 03

  Right. The pathway is different.

• 35:13Speaker 01

  Different.

• 35:14Speaker 03

  The progression is different. The mutations might be different. That, you know, nutrient, whatever, everything is different.

• 35:19Speaker 01

  Exactly. Every individual exposure that you've had, your particular DNA and how it's interacting with those exposures. And that is why it makes it really hard to generalize our treatments for cancer, even if we're like, but this is the same receptor or this is the same mutation, this is the same protein.

• 35:39Speaker 03

  Yeah.

• 35:39Speaker 01

  Why isn't this treatment working exactly the same?

• 35:42Speaker 03

  Yep.

• 35:42Speaker 01

  Right? So really, cancer is, I'm really wanting you to start talking, Erin. Because cancer is kind of our cells forgetting how to function as a multicellular organism.

• 36:00Speaker 03

  Yeah.

• 36:00Speaker 01

  It's our cells, all of a sudden, but not all of a sudden because it's a long process, but starting to live as parasites, as these like unicellular organisms that no longer abide by all of the rules that makes them good neighbors to all of the other cells around them.

• 36:15Speaker 03

  But they also do cooperate within a tumor.

• 36:18Speaker 01

  Ooh, I can't wait for you to tell me all about that, Erin. And they do, and they cooperate with that particular environment.

• 36:25Speaker 03

  Right.

• 36:25Speaker 01

  And they make it very conducive for themselves.

• 36:28Speaker 03

  Yeah.

• 36:28Speaker 01

  And themselves only. And they're leveraging our body systems in order to do this. So Erin, I'm hoping that you can shed some light on the evolution of cancers and why it is that we are so susceptible to these.

• 36:42Speaker 03

  It's so funny that you said shed some light because I literally say something just like that.

• 36:46Speaker 01

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• 37:21Speaker 02

  Hey, it's Niall Rogers, host of Before the Moment, a Lincoln original series. I'm driving across the country, meeting some of today's most fascinating artists. We're exploring the stories before the moment that changed everything. This week, I'm joined by rising star Sienna Spiral.

• 37:40Speaker 06

  My first ever In the World show was when I was 10, and I sang at a pub called the Georgian Devonshire. I was so nervous. I was 10, so they let me in only to sing my song, and then they kicked me out right after. And then I remember I wrote, I've been writing since I was 10, so I wrote this song called Lady in the Mirror. Made this little track with it, but I just like pressed it. And I remember I sang this song, and there was like five people in there. And I remember how myself I felt, and I felt like I understood myself and understood what I needed to do.

• 38:07Speaker 02

  So does that take us back to, I sing just? Just to know I'm alive.

• 38:11Speaker 06

  Hundred percent, hundred percent, in my whole life.

• 38:14Speaker 02

  Experience Before the Moment, a Lincoln original series on the iHeartRadio app, YouTube, or wherever you get your podcasts.

• 38:36Speaker 00

  Hey, my name is Kendra and I am 33. I was diagnosed with stage 3C ovarian cancer in 2024. My diagnosis came as a surprise as I didn't have any signs or symptoms to think that I needed to be seen for anything. I was just going in to get my IUD replaced and needed an ultrasound, and then they found the ovarian cancer. Sadly, ovarian cancer doesn't have a lot of noticeable signs or symptoms, and so it was a fluke that it was found. After being sent to gynecology oncology to figure out a treatment plan, I was sent off for some genetic testing where I found I was also BRCA1 positive. With the BRCA

• 39:18Speaker 00

  gene, I have an increased risk of cancers such as breast ovarian cancer, as well as pancreatic cancer and some other cancers. Along with getting myself genetically tested, my doctor also sent my cancer off to be genetically tested, where they were able to find a few different treatment plans that would be helpful that were specifically targeted towards my type of cancer. This has been an overwhelming and scary process, and I have learned so much about the medical research that has been done and the advancements that we've made, looking at genetics and how it impacts people's risks for cancer.

• 40:00Speaker 00

  Hi, my name is Michelle. I'm 42 years old and I live on Long Island, New York. My husband Ed was diagnosed with glioblastoma, which is the most aggressive form of brain cancer, in July of 2024 and passed away in October of 2025 at 44 years old. We're the parents of a teenage son and Ed was a talented radio producer, so speaking about his experience on a podcast is actually something that really connects to who he was in his professional life. Ed had a sinus infection and then for two weeks following had intermittent pressure headaches.

• 40:34Speaker 03

  Urgent care said it's probably a lingering sinus infection. And he went to his primary care doctor who said, let's get an MRI just in case, because why take the chance? So scheduled an MRI. A couple of days before the MRI, he came to me and said, this isn't getting any better. And I said, why don't you just go to the ER just for peace of mind? I actually Googled whether or not a headache was a good reason to go to the ER. And he drove himself and said, don't cancel our dinner plans. And three hours later, he called me and said, you need to get here now. They found something on the CAT scan. And thankfully, we only live five minutes from the hospital. It was an incredibly traumatic 14 and a half months.

• 41:18Speaker 03

  And when I say this was the shock of our lives, it's a tremendous understatement. There's so much I could discuss about our experience. But one thing that stands out is that glioblastoma is not common at our age. So it was so isolating going through this and him seeing that he was the youngest person in the waiting room every single time. When he was looking for support groups for himself, it was mostly people who were 20 to 30 years older. When I was looking for caregiver support groups, it was mostly children, taking care of parents, or retired couples. And we were like, where are all the people who are working full time, who had to put

• 42:01Speaker 03

  their careers on hold, who have to caregiver full time while also making sure they're school age children, routines are intact and have extracurricular activities to take their kids to? The worst was when people would see us and say, you're too young to be dealing with this. And I'm trying to navigate that as a widow right now. Apparently, the universe didn't get the memo that we're too young to be dealing with this.

• 42:47Speaker 03

  We learned last week that cancer has been our unwelcome companion for all of human history. Yeah. Ancient medical descriptions of tumors and fossilized hominid remains with probable cancerous growth, they defy the labeling of cancer as solely a disease of modernity. Mm-hmm. And yet, despite millennia of human evolution, despite the recent decades of cancer research, despite the thousands who have devoted their lives to finding a cure, despite the hundreds of thousands and millions who have also participated in finding this cure. Right. We still struggle to effectively treat, or prevent, or even define this disease. Yeah. Why? Why?

• 43:29Speaker 03

  To answer that, we have to rethink cancer from an entirely different perspective. Rather than seeing cancer as this single entity that can only be defeated through a full-scale attack, we can use evolution to grasp the nuance and complexity that drives cancer development. Which hopefully will also steer us away from that military language of wars and battles, implying winners and losers, and us versus them. Yes. As you just explained, Erin, cancer cells are a part of us. Why would cancer grow so out of control if that results in the death of its host and thus the cancer itself? Well... Why is cancer so common in humans? Shouldn't we have evolved to resist it?

• 44:12Speaker 03

  It just doesn't make sense. I mean, does it, though? Then again. Paraphrasing Theodosius Dobzhansky, "Nothing in cancer biology," he says "nothing in biology," "makes sense except in the light of evolution." I challenge you to find a paper on cancer evolution that does not reference Dobzhansky's essay. That quote? Yeah. So let's shine that evolutionary light on cancer. This is a story told in four parts. Okay. The first deals with seeking to understand the evolutionary drivers of cancer cells. Why do they proliferate? Why do they spread? The second involves the defenses that we have evolved to prevent or control cancerous growth.

• 44:56Speaker 03

  The third scans for patterns across the animal kingdom in cancer resistance and susceptibility. Okay. And the fourth and final part asks, how can we apply this evolutionary knowledge to design better strategies for cancer treatment today? Ugh, Aaron. I can't tell you. I've been waiting for this episode for so long. This episode really was like a shift for me in being like, oh, this is not some... I know you called cancer a parasite, but it's not. Like, it is just a product of evolution. Hmm. That's it. I love it. It doesn't want to survive. It just does because it happens to have evolved those certain traits. Okay. Anyway, okay. So, part one. Okay.

• 45:40Speaker 03

  When it comes to the deep evolutionary roots of cancer, our hominid fossils reveal the merest tip of the iceberg. In fact, even older specimens with suspected cancers on the order of tens of millions of years, like in the case of duck-billed dinosaur fossils, which show cancer, to hundreds of millions of years. We're still in iceberg tip territory. Okay. The true origins of cancer extend back to the first multicellular life. When life on Earth began roughly four billion years ago, single-celled organisms ruled the roost, and they did so for the next two billion years. During that unfathomably long period in which individual cells battled individual cells, cancer did not exist. That is so... I mean, like, it could not exist.

• 46:25Speaker 03

  It could not exist. No. Because by its very definition, uncontrolled growth of abnormal cells... cancer requires other "normal" cells to stand out in contrast. Uncontrolled growth is only uncontrolled in comparison to what is considered controlled. Right. So, it was only two billion years ago, when cells began to coalesce and coordinate to form multicellular organisms, that cancer was possible. Wow. Multicellularity is a great strategy. It's a great way to go.

• 46:54Speaker 01

  Yeah, it works pretty well.

• 46:55Speaker 03

  I mean, imagine, instead of doing everything yourself, you divvy up tasks like cleanup or resource gathering, and you can accomplish much more than you could on your own. It's true what they say, there's strength in numbers. Multicellularity depends on cooperation on a massive scale. We like to think of ourselves as individuals, as individual thinkers, you know, with our own lives.

• 47:17Speaker 01

  So unique.

• 47:19Speaker 03

  But really, what we are is a massive population of cells with different jobs and locations and genetic identities. And not all are human cells. We've got lots of non-human cells in there.

• 47:31Speaker 01

  Possibly more than our human cells.

• 47:32Speaker 03

  Possibly. This cooperation is really quite astounding, if you think about it. In her book, The Cheating Cell, researcher Athena Ectipus presents what she calls the multicellularity playbook.

• 47:44Speaker 01

  Okay.

• 47:45Speaker 03

  I like this in contrast to like, think about this in contrast to the hallmarks.

• 47:50Speaker 01

  Okay.

• 47:50Speaker 03

  The cancer hallmarks, the hallmarks of cancer. Number one, don't divide out of control. Number two, self-destruct if you're a threat.

• 47:58Speaker 01

  Yeah.

• 47:59Speaker 03

  Number three, share and transport resources. Number four, do your job, division of labor.

• 48:04Speaker 01

  Yeah.

• 48:05Speaker 03

  Number five, take care of the environment.

• 48:07Speaker 01

  Oh, if only we could all...

• 48:11Speaker 03

  Basically, just, I know.

• 48:12Speaker 01

  Follow the rules of multicellularity.

• 48:14Speaker 03

  I mean, you...

• 48:15Speaker 01

  Listen.

• 48:17Speaker 03

  There's too much we could even go into there. But basically, it comes down to do your job, be respectful, and everything's gonna be hunky-dory.

• 48:25Speaker 01

  We're all gonna be chill and living together.

• 48:27Speaker 03

  It's great.

• 48:28Speaker 01

  Clean your dishes out of the sink, put them in the dishwasher. Like, is it that hard?

• 48:31Speaker 03

  Just pick up after yourself, yeah. And of course, we know that things don't always go that way.

• 48:38Speaker 01

  No, they don't.

• 48:39Speaker 03

  They rarely always go that way. Cooperation is vulnerable to exploitation by cheaters. And when cells don't follow the multicellularity playbook, cancer can result. Cancer cells, they're not consciously cheating and intending to get a leg up on all these cooperative suckers. It's simply evolution. So our cells, as you said, are constantly replicating to grow, to develop, to replace damaged cells. And this process involves copying the DNA within ourselves. With all that copying, a few errors are bound to slip in there.

• 49:11Speaker 01

  Yeah.

• 49:12Speaker 03

  Most of the time, we've got these self-defense mechanisms or these little checkpoints, those mistakes are to make, you know, check up on things.

• 49:19Speaker 01

  Right.

• 49:19Speaker 03

  Maybe the mistakes are harmless, maybe they're repaired, or maybe the mistakes are too big and the cell is earmarked for destruction.

• 49:27Speaker 01

  Exactly.

• 49:27Speaker 03

  Yeah. But on occasion, those mutations will slide under the radar. And let's say that one of those mutations tells the cell to proliferate rapidly with no off switch. And another maybe helps it evade the defense mechanisms, whose job it is to catch these out of control cells. So now we've got this renegade cell with the gas pedal to the floor and the breakout of commission.

• 49:50Speaker 01

  Mm-hmm.

• 49:51Speaker 03

  In no time, that cell becomes two, then four, then eight, then 16, and so on.

• 49:56Speaker 01

  And that's how cell division works.

• 49:57Speaker 03

  Yep. And all of these daughter cells are then inheriting those same mutations. These cells, they're not playing by the rules of multicellularity playbook. And in an evolutionary sense, they're doing great.

• 50:10Speaker 01

  Yep.

• 50:10Speaker 03

  There's no conscious thought to like, I want to evade, I want to take these resources. Oh, that's a new resource? Let me take that. It's the cells that happen to evolve the mutations that allow them to take advantage of this environment.

• 50:21Speaker 01

  They are just growing because they can grow.

• 50:25Speaker 03

  Yep. Yep.

• 50:27Speaker 01

  That's it.

• 50:27Speaker 03

  And spread.

• 50:28Speaker 01

  And spread.

• 50:28Speaker 03

  Yeah.

• 50:28Speaker 01

  Because they can.

• 50:29Speaker 03

  It's because the mutations evolve.

• 50:31Speaker 01

  Yeah.

• 50:31Speaker 03

  And so ultimately, if this proliferation continues unchecked, it will result in the death of the entire organism, which includes the cancer cells themselves.

• 50:42Speaker 01

  Which is a bad thing.

• 50:43Speaker 03

  Right. So, we've got these cancer cells out competing normal cells, but if that ultimately kills the organism, how can that be evolution? Like, isn't that just a dead end?

• 50:55Speaker 03

  It is for that individual cancer.

• 50:57Speaker 01

  Yeah.

• 50:57Speaker 03

  Which will go extinct when its host dies.

• 50:59Speaker 01

  Yes.

• 51:00Speaker 03

  Extinction is not a new concept. And this is also asterisk for if you're transmissible cancer.

• 51:05Speaker 01

  Right.

• 51:05Speaker 03

  Another story.

• 51:05Speaker 01

  That's a whole nother story.

• 51:06Speaker 03

  But like dinosaurs have gone extinct.

• 51:09Speaker 01

  Yeah.

• 51:09Speaker 03

  Humans have killed off many different species.

• 51:12Speaker 01

  So many species we have made go extinct.

• 51:14Speaker 03

  You know, how many thousands of years?

• 51:15Speaker 01

  Yeah. It's part of the process of evolution.

• 51:17Speaker 03

  It's part of the process of evolution. Right. And I think it also is important to remember that evolution works on different time scales.

• 51:25Speaker 01

  Yes.

• 51:26Speaker 03

  Yes. So to quote from Ectipus's The Cheating Cell, quote, "From the perspective of our bodies, cancer is a threat to our survival and well-being. From the perspective of the cell, cancer cells are only doing what every other living thing on this planet does, evolving in response to the ecological conditions they are in, sometimes in ways that are detrimental to the system of which they are a part." End quote. It's just.

• 51:52Speaker 01

  It's just evolution.

• 51:53Speaker 03

  It's just evolution.

• 51:54Speaker 01

  Yeah.

• 51:54Speaker 03

  And I'm not, we're not saying that to minimize it.

• 51:56Speaker 01

  No.

• 51:57Speaker 03

  But just to explain, like, this is not some, you know, parasite that's coming in and wanting to take advantage of this and doing this and that.

• 52:05Speaker 01

  But I mean, even parasites are just evolution.

• 52:07Speaker 03

  Yeah, exactly.

• 52:08Speaker 01

  Right? Like, that's the thing. They're not, like, they don't have agency. They're not trying to kill us. It's just that they are, those particular cells are surviving.

• 52:16Speaker 03

  They're surviving.

• 52:16Speaker 01

  That is all they are doing.

• 52:17Speaker 03

  And the ones that do survive are the ones that have the right characteristics.

• 52:23Speaker 01

  The right tools, the right characteristics.

• 52:24Speaker 03

  In that particular environment.

• 52:25Speaker 01

  It's that environment at that time. Yeah.

• 52:29Speaker 03

  Yeah.

• 52:29Speaker 01

  And, and evolution is working on that population of cells.

• 52:32Speaker 03

  Right. So, because cancer is not a one-time event.

• 52:34Speaker 01

  No.

• 52:35Speaker 03

  Those renegade cells will continue to evolve as long as there is genetic variation, which is why we see diversity within tumors. Nor is cancer just cancer cells. The tumor microenvironment both influences and is influenced by the cells that comprise it, both cancerous and non-cancerous. There's collagen to hold the tumor together, blood vessels that deliver resources, even immune cells that have been reprogrammed by the cancer cells to tell other cells, "Don't worry about it, just move along." Some cancer cells might be more clonal, so like genetically identical than others, but genetic and tissue diversity is a feature of cancer, which is what makes it so difficult to treat. Cancer is not a homogenous tissue. No.

• 53:18Speaker 03

  It is instead an evolving, dynamic mass of genetically diverse cells. Yep. Within that mass, some cells might be super susceptible to a type of treatment, while others are more inherently resistant. If that treatment is administered, you would expect the resistant cells to increase in number, because those are the ones left over. This is why resistance emerges so often after cancer treatment, and why oncologists combine different treatments. Right. And again, these cancer cells, they're not replicating uncontrollably or evolving resistance because they're evil or want to succeed. Or they're trying to kill you. They have simply inherited the instructions to do so. Mm-hmm. Part two. Okay. Defense against cancer.

• 54:02Speaker 03

  That chaotic growth, the seizing of resources, the resistance to destruction, these are not new weapons created by cancer cells. These are all qualities that our normal, cooperative cells already possess. Yeah. If these features can do such harm when expressed in a cancer cell, why do they evolve at all? Because proliferation and differentiation are foundational to our growth and development. When we're growing as embryos, then fetuses, then infants, healing a wound, fighting an infection, going through puberty, reproducing, replacing the lining of our intestinal tractor's skin, proliferation, differentiation, movement, and resource utilization, these are what makes us multicellular organisms.

• 54:47Speaker 03

  If our cells exert too strong of a control over these processes, our development or our fertility might be negatively impacted as a result. So think back to our second episode in our pregnancy series when we talked about the placenta. Yeah. And there is this like kind of push-pull where it's like, this is a really challenging experience for your body to be like, okay, this thing is growing inside me and it's kind of like me, but it's not quite like me. And so how much do I give and take? And it's a little bit of a balance there. Right. And it's sometimes hard to strike. Yeah. And so there's this thought that like, uh, cancer is one of the costs of higher fertility.

• 55:25Speaker 01

  Oh, that's so interesting.

• 55:26Speaker 03

  For things that are like you but not quite like you.

• 55:29Speaker 01

  A little off. Just a little off. Oh, that's super interesting, Erin.

• 55:31Speaker 03

  Right. It's a tightrope.

• 55:32Speaker 01

  Yeah.

• 55:33Speaker 03

  So if these processes are allowed to continue unchecked, though, cancer might be the outcome. So it's either you are hold, you know, too tight of a control over them and then you'd stagnation.

• 55:46Speaker 01

  Right.

• 55:46Speaker 03

  And underdevelopment, or not enough control.

• 55:49Speaker 01

  And then you end up with cancer.

• 55:51Speaker 03

  Yeah.

• 55:51Speaker 01

  Oh, that's so interesting, Erin.

• 55:53Speaker 03

  This is the crux of cancer. The constant tightrope walk that we do as organisms to balance chaotic growth with stagnation. As Ektipis puts it, quote, "This leads to the counterintuitive conclusion that the optimal level of cancer risk for an organism is not zero."

• 56:12Speaker 01

  Right. Yeah.

• 56:14Speaker 03

  That is, to me, that's like the bottom line of everything.

• 56:17Speaker 01

  Yeah.

• 56:18Speaker 03

  That cancer is the consequence of multicellular life.

• 56:22Speaker 01

  Yeah.

• 56:22Speaker 03

  For growth and division, reproduction.

• 56:24Speaker 01

  Right. It's all of the things that we already do. It's just doing too much.

• 56:31Speaker 03

  Yeah. "The near ubiquity of cancer across multicellular organisms demonstrates that cancer is an unavoidable consequence of complex multicellular life. One that can shorten lifespan and impact fertility to a considerable degree." Just because we have a multicellularity playbook doesn't mean everyone follows these rules. And so we've evolved different strategies to catch and eliminate those cheaters. The first is intrinsic. So our cells, you'd kind of talked about this, our cells contain within them these intrinsic mechanisms to monitor for any funny business. Big mistakes in DNA transcription, wonky proteins, or something else that signals that the cell might not be following the multicellularity playbook. If something abnormal is detected, that information is processed and then a quote-unquote

• 57:16Speaker 03

  "decision" is made, there's no conscious thought here.

• 57:19Speaker 01

  Right, right, right.

• 57:20Speaker 03

  Just using it as a shortcut. Can the cell be repaired?

• 57:23Speaker 01

  Right.

• 57:23Speaker 03

  Should we shut down replication until the error is fixed? Should the cell self-destruct? This is where something like TP53 comes in. Our famous tumor suppressor gene, also known as the guardian of the genome, which I really love.

• 57:36Speaker 01

  I know. I just think it sounds so new. Noble.

• 57:38Speaker 03

  I know. So TP53 takes in all this information and it initiates the appropriate response. And that's just one example

• 57:46Speaker 01

  Right.

• 57:46Speaker 03

  of our intrinsic defenses against cancer. We've got many other strategies like preventing or repairing DNA copying mistakes in the first place. And then in addition to these intrinsic mechanisms, we've also got the neighborhood watch. This is pretty much what it sounds like. Cells keep an eye on their close neighbors for any sign that something suspicious is going on, looking little binoculars through the window like, what time is it?

• 58:06Speaker 01

  It's just like that, what's that app?

• 58:08Speaker 03

  Who's coming in?

• 58:08Speaker 01

  That everyone's using?

• 58:09Speaker 03

  Nextdoor?

• 58:09Speaker 01

  Nextdoor?

• 58:10Speaker 03

  Yeah. It's just, it is just like that.

• 58:12Speaker 01

  Yeah, it is.

• 58:13Speaker 03

  And so for the most part, our cells are quite sensitive to self-destruction.

• 58:17Speaker 01

  Yeah.

• 58:17Speaker 03

  You just give them a funny look and they're like, okay, fine, I guess I'll just self-destruct.

• 58:21Speaker 01

  Yeah.

• 58:22Speaker 03

  They're committed to cooperation. And so often, it's, it's not so much like that the neighbor cells have to be like, self-destruct. It's more just like if the neighbor cell is like, you're not.

• 58:34Speaker 01

  You're not really pulling your weight, man.

• 58:36Speaker 03

  Right, like they want constant positive reinforcement.

• 58:38Speaker 01

  Yeah.

• 58:39Speaker 03

  And so if their neighbor cell is like, I'm just, it's not, it's not doing it for me.

• 58:42Speaker 01

  It's not me, it's you.

• 58:44Speaker 03

  Right. Then they're like, okay, I guess I'll just self-destruct.

• 58:47Speaker 01

  I'm out here, okay.

• 58:48Speaker 03

  Yeah. And, um, and the neighbor cells will eventually be like, you need to self-destruct.

• 58:53Speaker 01

  If it gets bad.

• 58:54Speaker 03

  If it's like, if they're like, come on, take a hint. So, okay, so our cells have got these internal monitoring systems. Their, their neighbors are keeping a watch on them. And then there's this more global line of defense, the immune system.

• 59:05Speaker 01

  Right.

• 59:05Speaker 03

  Our immune system is constantly scrutinizing cells for any signs of cheating, like excessive proliferation, consuming too many resources, and avoiding instructions to self-destruct. And one of the ways our immune systems do this is to detect tumor antigens, which are these proteins expressed on the surface of certain cancer cells. The immune system reads as a signal that the cell is behaving inappropriately. And if they detect one of these antigens, they can tell other cells, search and destroy anything expressing this antigen. It's basically like what they do to viruses.

• 59:34Speaker 01

  Exactly.

• 59:35Speaker 03

  Destroy. Yeah. So these three primary means of cancer suppression are continuously monitoring for any signs of trouble. And when you think about the 30 trillion or so cells in our body, I have a citation for that.

• 59:49Speaker 01

  Oh, yeah, I saw 30 to 40.

• 59:50Speaker 03

  Yeah.

• 59:51Speaker 01

  Yeah.

• 59:51Speaker 03

  Yeah.

• 59:51Speaker 01

  It's bananas.

• 59:52Speaker 03

  And I was like, it is also brilliant to write this paper. You will be cited so frequently. Because everyone's gonna be like, how many cells in the body?

• 59:59Speaker 01

  How many cells?

• 1:00:00Speaker 03

  30 trillion. Let me find it. Let me find it on Google Scholar. Yeah. But when you think about all these cells, it's pretty astonishing how good of a job our body does most of the time when it comes to monitoring for any signs of disruption.

• 1:00:12Speaker 01

  Seriously. And like, if you really know how many times we make mistakes in DNA replication.

• 1:00:17Speaker 03

  Yeah.

• 1:00:18Speaker 01

  It is fascinating that it doesn't, that cancers and other deleterious mutations don't arise more frequently.

• 1:00:24Speaker 03

  Right. I mean, and this is a reflection of millions of years of evolution.

• 1:00:30Speaker 01

  Yeah.

• 1:00:30Speaker 03

  Billions. When we look at an age distribution of cancer diagnoses, most happen later in life. And comparatively, and comparatively few happen in childhood, despite childhood being a time of rapid cell proliferation and differentiation as we grow and mature.

• 1:00:46Speaker 01

  Right.

• 1:00:47Speaker 03

  There is stronger selection for those cancer suppression mechanisms at an early age.

• 1:00:52Speaker 01

  Oh, that makes sense.

• 1:00:52Speaker 03

  Because the cost of cancer through an evolutionary lens, like the fitness cost, is greater. That selection relaxes a bit as we get older. And to be clear, I'm not suggesting that it's worse than when cancer happens in a child compared to an adult. Cancer is awful no matter when it happens. I'm simply saying that these cancer defense mechanisms were more likely to be passed down because they conferred a benefit for survival and reproduction, especially earlier in life.

• 1:01:17Speaker 01

  To our whole organism.

• 1:01:19Speaker 03

  To our whole organism.

• 1:01:20Speaker 01

  Right.

• 1:01:20Speaker 03

  Yes.

• 1:01:21Speaker 01

  Yeah.

• 1:01:21Speaker 03

  And remember, again, it's a tightrope. These defense mechanisms don't always function perfectly because there's a trade-off between chaos and stagnation. If having a bigger body means better survival or reproductive viability, then you don't want to restrict proliferation or differentiation too early.

• 1:01:37Speaker 01

  No.

• 1:01:38Speaker 03

  Same with wound healing.

• 1:01:39Speaker 01

  Mm-hmm.

• 1:01:40Speaker 03

  Same with tissue repair, making new blood cells, and so on. How do different species balance this trade-off? Like, what patterns exist? Part three.

• 1:01:49Speaker 01

  Okay.

• 1:01:50Speaker 03

  Cancer across the animal kingdom.

• 1:01:51Speaker 01

  Okay.

• 1:01:52Speaker 03

  Uh, there are cancerous growths in plants.

• 1:01:55Speaker 01

  Yes.

• 1:01:56Speaker 03

  And fungi. I'm not gonna talk about them.

• 1:01:57Speaker 01

  They're so interesting and cool looking though.

• 1:01:59Speaker 03

  I know. They're very cool, but it's, that's too big for...

• 1:02:02Speaker 01

  Oh, yeah.

• 1:02:02Speaker 03

  This is already too big.

• 1:02:03Speaker 01

  Are you kidding?

• 1:02:03Speaker 03

  Yeah, I know, I know.

• 1:02:05Speaker 01

  But it is true. It's all multicellular organisms and that includes plants.

• 1:02:08Speaker 03

  Yeah, yeah. Almost all. But I read some stuff about sponges that I took out. But anyway.

• 1:02:13Speaker 01

  Sponges, though.

• 1:02:14Speaker 03

  They just sort of like pinch it off and they're like...

• 1:02:15Speaker 01

  They're like, "You don't need anymore."

• 1:02:17Speaker 03

  Bye.

• 1:02:18Speaker 01

  Yeah, yeah. That's cool.

• 1:02:19Speaker 03

  Kind of like what our guts do a little bit. It's, it's very cool.

• 1:02:22Speaker 01

  Yeah.

• 1:02:22Speaker 03

  So, knowing what we know about cancers, what are some patterns we think we might find?

• 1:02:27Speaker 01

  Yeah.

• 1:02:28Speaker 03

  Okay, broadly speaking, cancer happens when a cell acquires mutations that A, let it throw out that multicellularity playbook, and B, escape detection and destruction by cancer suppression mechanisms. All it takes for cancer to develop is one cell going rogue and the right environment.

• 1:02:45Speaker 01

  And everything else, yeah, but...

• 1:02:46Speaker 03

  But you know what I mean.

• 1:02:47Speaker 01

  Exactly.

• 1:02:47Speaker 03

  You still need the initial...

• 1:02:49Speaker 01

  You need that.

• 1:02:49Speaker 03

  You need the potential.

• 1:02:50Speaker 01

  Yes.

• 1:02:50Speaker 03

  Yeah. So you might expect that the more cells there are, the greater the risk of cancer.

• 1:02:56Speaker 01

  Do we see that, Aaron?

• 1:02:58Speaker 03

  Okay, so if this were the case, what we might expect to find is that elephants, blue whales, rhinos, and other large-bodied species should have higher rates of cancer than small ones, like mice, bats, small birds. And longer-lived species, like giant tortoises and humans, whose cells have a lot longer to accumulate cancerous mutations, should also have a higher risk of cancer compared to those with relatively short or comparatively short lifespans.

• 1:03:25Speaker 01

  Okay.

• 1:03:25Speaker 03

  Like shrews and hedgehogs.

• 1:03:27Speaker 01

  Okay.

• 1:03:28Speaker 03

  That's not what we find.

• 1:03:29Speaker 01

  Interesting, yes.

• 1:03:31Speaker 03

  In fact, there seems to be no correlation at all between longevity, body size, and cancer across species.

• 1:03:39Speaker 01

  Huh.

• 1:03:40Speaker 03

  So this surprising finding has a name. It's called pitos paradox.

• 1:03:44Speaker 01

  Oh, I've heard of this. Yeah, yeah, I know pitos paradox.

• 1:03:46Speaker 03

  Pitos paradox. So elephants, despite having 100 times the amount of cells that humans do, do not have 100 times the risk of cancer.

• 1:03:55Speaker 01

  Yeah.

• 1:03:55Speaker 03

  In fact, elephants are less likely to develop cancer compared to humans.

• 1:03:59Speaker 01

  Interesting.

• 1:04:00Speaker 03

  On the other end of the scale, mice are more likely to develop cancer than humans are.

• 1:04:04Speaker 01

  Really?

• 1:04:05Speaker 03

  Really.

• 1:04:06Speaker 01

  No one talks about that.

• 1:04:07Speaker 03

  I know.

• 1:04:07Speaker 01

  Not just the mice we grow in life. Labs, I presume.

• 1:04:09Speaker 03

  I don't, I mean, so this is where, don't get me started on like the data viability. There are multiple papers that discuss about like the limitations of Pedo's paradox and the observations that have been used to formulate it. Anyway.

• 1:04:19Speaker 01

  Okay.

• 1:04:20Speaker 03

  So, however, though, within a species, the pattern is there. The expected pattern that we see. So bigger dogs are more likely to develop cancer than smaller dogs. Taller humans are more likely to develop cancer compared to shorter humans. And the same goes for age, again, within a species.

• 1:04:40Speaker 01

  Okay.

• 1:04:40Speaker 03

  Yeah.

• 1:04:41Speaker 01

  How interesting.

• 1:04:42Speaker 03

  Yeah. So why might this pattern not hold across species?

• 1:04:47Speaker 01

  You gotta have, they gotta have something else going on.

• 1:04:49Speaker 03

  There's gotta, I mean.

• 1:04:49Speaker 01

  Some other protective mechanism.

• 1:04:51Speaker 03

  Many different possible answers, right? Larger species might have lower mutation rates overall. They might have more tumor suppressor genes. This actually has been found in elephants who have 20 copies of TP53 compared to humans, two copies.

• 1:05:05Speaker 01

  I learned that once.

• 1:05:05Speaker 03

  Yeah.

• 1:05:06Speaker 01

  I knew that one.

• 1:05:09Speaker 01

  Obviously forgot it, but I learned that one.

• 1:05:11Speaker 03

  It's, it blew my mind.

• 1:05:12Speaker 01

  Yeah.

• 1:05:12Speaker 03

  It blew my mind. Uh, there, maybe the, their species' immune systems could be more tuned in to precancerous or cancerous cells. Their cells might be more sensitive to a self-destruct signal. It's even been suggested that larger animals develop larger tumors that then themselves are destroyed by cancerous cells, where it's like tumor infighting.

• 1:05:32Speaker 01

  Interesting.

• 1:05:32Speaker 03

  Kind of a thing. Like, there's something about like, yeah.

• 1:05:35Speaker 01

  Just in the way that it interacts with their immune system is gonna be different.

• 1:05:38Speaker 03

  Something like that, yeah.

• 1:05:39Speaker 01

  Interesting.

• 1:05:40Speaker 03

  So in short, yeah, there are a number of different hypotheses as to why larger-bodied and longer-lived species have less cancer than we'd expect. Pedo's paradox might also reveal different trade-offs in life history strategies. So take a mouse, for example, which matures to reproductive age pretty quickly. To take advantage of that quick development time, you might wanna step on the proliferation gas, so to speak, even if that comes with a higher risk of cancer. And this is actually what we have found when it comes to chicken farming. Chickens that are selected for early egg-laying and higher production tend to have higher rates of ovarian cancer.

• 1:06:16Speaker 01

  Interesting.

• 1:06:17Speaker 03

  Mm hmm.

• 1:06:17Speaker 01

  Because they're like, make more eggs.

• 1:06:19Speaker 03

  Make more, make more, proliferate, proliferate, proliferate. And elephants which mature later on might invest more in cellular watchfulness earlier in life.

• 1:06:29Speaker 01

  Interesting.

• 1:06:30Speaker 03

  Just to make sure that they survive to reproductive age.

• 1:06:32Speaker 01

  Right, of course.

• 1:06:32Speaker 03

  So, Peters paradox has been revisited repeatedly since it was first introduced in the 1970s. And researchers have argued that there is no paradox if you analyze the data this way, or the paradox grows stronger if you analyze it that way, or depending on where you're getting your data and all this stuff. But there seems to be no getting around the observation that from the existing data that we have, cancer risk is lower than we would expect in larger bodied and longer lived species.

• 1:06:59Speaker 01

  Okay.

• 1:07:00Speaker 03

  Beyond Peters paradox, there are a few other patterns that researchers have observed. Birds and reptiles tend to have less cancer than placental mammals. Species in carnivora, mammals that eat flesh, tend to have higher cancer risk. This might be because of biomagnification, so like carcinogenic compounds have accumulated at the top of the food chain, a low fiber and high fat diet, and

• 1:07:23Speaker 01

  Yep.

• 1:07:23Speaker 03

  potentially cancer causing pathogens found in raw meat.

• 1:07:26Speaker 01

  Interesting, okay.

• 1:07:27Speaker 03

  Yeah.

• 1:07:27Speaker 01

  Cool, cool.

• 1:07:28Speaker 03

  Deer that grow large antlers every year, rapid cell proliferation, tend to have higher rates of cancer. And there's some other stuff about like sexually selected traits like that that involve

• 1:07:39Speaker 01

  Oh, that's so interesting.

• 1:07:40Speaker 03

  making big things.

• 1:07:41Speaker 01

  Yeah.

• 1:07:42Speaker 03

  And species that have undergone a genetic bottleneck, like the Santa Catalina Island foxes, tend to have higher rates of cancer. Prevalence for them is like greater than 50%.

• 1:07:52Speaker 01

  Really?

• 1:07:54Speaker 03

  So that suggests that genetic diversity, especially when it comes to immune diversity, is really important when it comes to being protective against cancer.

• 1:08:02Speaker 01

  There's so many levels that I'm loving this, Erin, but also just, I feel like I have seen on the internet, people being like, but cancer only happens in humans.

• 1:08:11Speaker 03

  No, no, no.

• 1:08:11Speaker 01

  And like, just the diversity already that you've said.

• 1:08:14Speaker 03

  Oh, there's, yeah.

• 1:08:16Speaker 01

  I know.

• 1:08:17Speaker 03

  I know.

• 1:08:17Speaker 01

  You know the internet.

• 1:08:18Speaker 03

  I know, I do know the internet. I'm familiar.

• 1:08:22Speaker 01

  You've heard of it?

• 1:08:23Speaker 03

  I have heard of it. We're quite close.

• 1:08:27Speaker 03

  There's also other environmental or developmental drivers that could play a role in cancer risk across species. You know, if you're a species that's exposed a lot to UV radiation, maybe you're more likely to get cancer, maybe you're more likely to evolve defense.

• 1:08:41Speaker 01

  Defense is against that kind. Yeah, yeah.

• 1:08:43Speaker 03

  Right. The rate of healing might be positively associated with cancer risk. So if you're a fast healer, you might have higher risk of cancer.

• 1:08:50Speaker 01

  Because again, the like immune system mechanisms and the inflammatory process and the wound healing process uses a lot of those same features that cancers exploit.

• 1:08:58Speaker 03

  Yep.

• 1:08:58Speaker 01

  Kind of a thing.

• 1:08:59Speaker 03

  Yep, yep. And this is by no means an exhaustive list of the patterns that we see in cancer risk across the animal kingdom.

• 1:09:06Speaker 01

  Yeah.

• 1:09:06Speaker 03

  Nor does it fully explain the lifetime cancer risk in humans of 40%. Because even though we have these mechanisms that lower our risk of cancer, they don't take it to zero. And we talked about why that's probably not possible, right? The ideal risk for cancer is not zero.

• 1:09:23Speaker 01

  From an evolutionary perspective.

• 1:09:24Speaker 03

  From an evolutionary perspective when it comes to proliferation and differentiation.

• 1:09:27Speaker 01

  Right.

• 1:09:28Speaker 03

  But 40% might also reflect an evolutionary mismatch. Cancer is a consequence of multicellularity, yes, but the environment that we live in now is different than the one in which we evolved.

• 1:09:42Speaker 01

  Exactly.

• 1:09:42Speaker 03

  Things like cigarettes, processed meats, our sedentary lifestyles, our increased longevity, all of these things lead to a higher risk of cancer.

• 1:09:50Speaker 01

  Alcohol.

• 1:09:51Speaker 03

  Alcohol. And correspondingly, they lead to a need for a better approach to treatment. Part four.

• 1:09:59Speaker 01

  Okay.

• 1:10:00Speaker 03

  How can we apply what we know about cancer evolution to design treatments that outmaneuver rather than outright attack cancer? Even if you had never heard of treatment-resistant cancer before, the concept of resistance would probably be familiar to you, right? Antibiotic-resistant bacteria like MRSA or pesticide-resistant insects show us that resistance is a useful and expected trait that emerges in a biological target after a powerful onslaught.

• 1:10:27Speaker 01

  In the context of evolution, Erin.

• 1:10:29Speaker 03

  In the context of evolution. It's the same old story, right?

• 1:10:32Speaker 01

  Yeah.

• 1:10:32Speaker 03

  You target a susceptible population with some type of treatment, maybe that's penicillin, maybe that's DDT, maybe that's chemotherapy, maybe that wipes them all out. Or maybe a few invulnerable individuals remain. Those few multiply into many, and now you've got a fully resistant population against which you are powerless. This can happen in an individual receiving cancer treatment. Over time, the cancer may stop responding to those therapies. And this is a major issue in cancer that contributes to significant mortality every year, and we've struggled. We continue to struggle to contend with it. So faced with this substantial challenge, some cancer researchers have taken inspiration

• 1:11:16Speaker 03

  from other fields outside of cancer.

• 1:11:19Speaker 01

  Cancer?

• 1:11:20Speaker 03

  Like agriculture.

• 1:11:21Speaker 01

  Okay.

• 1:11:22Speaker 03

  To devise ways to minimize the emergence of resistance in the first place.

• 1:11:27Speaker 01

  Okay.

• 1:11:28Speaker 03

  One approach called adaptive therapy is modeled after integrated pest management.

• 1:11:32Speaker 01

  Integrated pest management?

• 1:11:34Speaker 03

  Yeah. Yeah. Which is an agricultural...

• 1:11:38Speaker 01

  What a throwback.

• 1:11:39Speaker 03

  I know. So integrated pest management is an agricultural technique that assumes resistance will eventually evolve, and so you delay the inevitable as much as you can. You utilize small doses rather than massive blasts with a goal of long-term control rather than eradication. Adaptive therapy, which is the cancer version of this, is intended to keep cancer cells sensitive to the drugs, and it has the added benefit of doing less damage to the surrounding tissue. The key is monitoring and adjusting the dose or timing according to how the tumor is responding. So if the tumor grows, you might want to increase the dose. If the tumor shrinks, lower the dose or just stop giving some meds.

• 1:12:21Speaker 03

  If it stays the same, either, you know, keep the dose the same or back off a little. It works, I mean, it's basically like a thermostat.

• 1:12:29Speaker 01

  Right.

• 1:12:30Speaker 03

  You're just like, okay, how do we get to 72?

• 1:12:32Speaker 01

  You're not trying to get rid of anything. You're just trying to not let it get any bigger.

• 1:12:36Speaker 03

  Yeah. And sometimes, maybe getting rid of something means getting your immune system to step in. Sometimes it means just like slowing things down.

• 1:12:47Speaker 01

  Right.

• 1:12:48Speaker 03

  Right? And so by employing this approach, you're selecting for slower dividing cells and you're relaxing that pressure to develop resistance and for resistance to be the key defining trait of this tumor now. Resistance mechanisms can be really costly to maintain. So if there's no need for them, those resistant cells might be outcompeted by sensitive ones. I came across a great analogy explaining this that I really, I really like. So think about like a big bulky umbrella.

• 1:13:14Speaker 01

  Okay.

• 1:13:15Speaker 03

  This is our resistance mechanism.

• 1:13:16Speaker 01

  Okay.

• 1:13:17Speaker 03

  It's heavy, it's annoying, you have to lug it around everywhere with you.

• 1:13:21Speaker 01

  Always forget it.

• 1:13:21Speaker 03

  Always forget it. If it's raining all the time, i.e. big doses of chemotherapy, the inconvenience is totally worth it.

• 1:13:28Speaker 01

  Hundred percent.

• 1:13:28Speaker 03

  And you're probably not going to want to leave it somewhere.

• 1:13:30Speaker 01

  Yeah.

• 1:13:31Speaker 03

  But if it's mostly sunny or just occasional drizzles, you're like, you're going to forget it at a cafe and not think about it again.

• 1:13:36Speaker 01

  I'm just going to just wear my raincoat.

• 1:13:37Speaker 03

  Right.

• 1:13:37Speaker 01

  It's going to be fine.

• 1:13:38Speaker 03

  And so resistance can also like, you can, cells can also evolve to no longer be resistant.

• 1:13:43Speaker 01

  Right.

• 1:13:44Speaker 03

  If there's not that pressure there to, to maintain resistance. So the beauty of adaptive therapy is that it's both generalizable and personal.

• 1:13:52Speaker 01

  Hmm.

• 1:13:53Speaker 03

  Right? You can use this with any existing, theoretically, can use this with any existing drug or treatment. And you're constantly tweaking the dose or timing based on how that individual tumor is responding.

• 1:14:04Speaker 01

  And it could be with any drug, right? Any drug that initially shows a benefit.

• 1:14:08Speaker 03

  Yes.

• 1:14:08Speaker 01

  You could do it with.

• 1:14:09Speaker 03

  You could do that with.

• 1:14:10Speaker 01

  Yeah.

• 1:14:11Speaker 03

  So, sounds great in theory. Is there any clinical evidence to back it up?

• 1:14:15Speaker 01

  Tell me.

• 1:14:16Speaker 03

  There is. The first clinical trial testing adaptive therapy was conducted 10 years ago, in 2016, on people with metastatic prostate cancer, whose cancer was no longer responding to hormone therapy. Those who received adaptive therapy had a median time to progression of 27 months.

• 1:14:33Speaker 01

  Okay.

• 1:14:33Speaker 03

  Compared to the 16 and a half months time to progression with standard treatment.

• 1:14:37Speaker 01

  Okay.

• 1:14:37Speaker 03

  So that's an extra 11 months, 10 months, 11 months. That's huge.

• 1:14:41Speaker 01

  Huge.

• 1:14:41Speaker 03

  Huge. So it slowed tumor growth in that way. It, it actually slowed the progression of the disease. And with adaptive therapy, the chemotherapy dose was cut in half, suggesting that this approach could lead to fewer side effects and lower medical costs, which is a concern in this country. Since that first trial, a handful of others have begun on prostate and ovarian cancer, and several of which are still underway, or I think in the works right now. But even though it's early days, adaptive therapy seems like a really promising area of cancer research. And it's important to point out that this is not for every case of cancer. Some cancers are going to respond better to some therapies than others.

• 1:15:23Speaker 03

  And researchers have devised different criteria for determining when a cancer might be treated with an aggressive versus an adaptive approach. What is going to result in the outcome that we most want, or like the ideal outcome? Yeah. But especially when it comes to cases where a cure seems unlikely, adaptive therapy may be able to control or delay progression. Another tactic is decoy drugs. Have you come across this? No. Okay, love this. So these are used for treatment-resistant cancers. And I also don't, like, I haven't read extensively on the existing literature, but so like, this is more of like the, as it was explained in a theoretical basis.

• 1:16:03Speaker 03

  But resistant cells, so they've, there are some resistance that involves evolving pumps to pump out the chemotherapy before it can do any harm. Because chemotherapy, I know we'll talk about it next week, but basically, its goal is to kill cells. It's just killing cells. It's killing cells. And so it's like, this is a toxic thing, pump that out. Get it out. Yeah. And so the idea with these pumps is that they pump out the chemotherapy drugs before it can do any harm, and that's how resistance works in those cells. These decoy drugs can take advantage of that. Ah. They don't do anything to the cancer, but they appear like dangerous chemicals. So those cells continuously pump them out. They're like, oh, my gosh, it's coming, it's gonna kill me, it's gonna kill me, I'm gonna pump it out, pump it out.

• 1:16:44Speaker 03

  This is constant work, exhausts the cells, it depletes resources, and it makes them expend too much energy to replicate. And so the goal with these therapies- Is not to actually do anything to the cells, except just keep them busy? Keep them busy. That's so interesting. Exhaust them. So it's not, it's, it's not to eradicate, it's not to destroy, it's just to anticipate cancer's next move, or even guide that next move. How interesting, Erin. For instance, there's one thought is that cancer cells become more likely to invade to a new area if their tumor environment becomes hostile or resource depleted, like what would happen with aggressive chemo.

• 1:17:21Speaker 01

  And radiation.

• 1:17:22Speaker 03

  And radiation. And so there's this idea that like maybe maintaining that tumor, and again, this is very dependent upon the individual, the cancer, but maintaining that tumor at that size, maybe that would prevent the cancer from spreading. So instead of shrinking the tumor, instead of attacking the tumor, we just keep it content.

• 1:17:41Speaker 01

  Keep it how it is.

• 1:17:42Speaker 03

  Yeah.

• 1:17:43Speaker 01

  Yeah.

• 1:17:43Speaker 03

  So that the cells don't.

• 1:17:44Speaker 01

  Just don't let it do its invasion thing.

• 1:17:46Speaker 03

  Yep, yeah. Or what if we directed evolution so that benign cells, quote unquote, were encouraged to grow over malignant ones? How do you kind of do that? You can kind of lead it down and like into an alley and then trap it, cancer in that way. I mean, that, this is sort of the idea.

• 1:18:03Speaker 01

  Yeah.

• 1:18:04Speaker 03

  We could also support our own body's ability to detect or eliminate cancerous cells, which I'm assuming you're going to talk about next week. It is extremely encouraging to see the incorporation of evolutionary principles into cancer treatment, and it's something that is long overdue. So there was an analysis published in 2011 where authors estimated that 1% of all papers about cancer recurrence or resistance that were published since the 1980s mentioned anything about evolution. 1%.

• 1:18:34Speaker 01

  Oh, dear.

• 1:18:35Speaker 03

  Talked about evolution. Ongoing research on cancer evolution, tumor ecology, and adaptive therapy, it holds the power to transform the way that we understand and treat cancer. And I'm really excited to see where this research will take us. But only looking back on the journey that brought us here, can we appreciate how far we've already come?

• 1:18:56Speaker 01

  Oh, this is so true, Erin.

• 1:18:58Speaker 03

  So stay tuned for next week when we talk about cancer treatment.

• 1:19:02Speaker 01

  Another great cliffhanger.

• 1:19:04Speaker 03

  Thank you.

• 1:19:05Speaker 01

  What a journey, Erin.

• 1:19:07Speaker 03

  I, I just, it really helped me to think of cancer cells as just successful in an evolutionary context, using the tools that they already had.

• 1:19:18Speaker 01

  Yeah.

• 1:19:18Speaker 03

  In our normal cells.

• 1:19:19Speaker 01

  Which I honestly still, like, that is why I, they, they seem. Like a population of bacteria to me.

• 1:19:25Speaker 03

  But like, I know, I know.

• 1:19:26Speaker 01

  Cause they're us. And so they have all of our traits and all of this.

• 1:19:30Speaker 03

  Bacterial cells have, you know, certain toxins or certain whatever.

• 1:19:34Speaker 01

  They have other things that they, and we don't, right?

• 1:19:35Speaker 03

  And they're, the cancer cells are working with the toolkit.

• 1:19:39Speaker 01

  Yeah.

• 1:19:39Speaker 03

  That every single one of our cells already has.

• 1:19:42Speaker 01

  Yeah, yeah, yeah, it's true.

• 1:19:43Speaker 03

  That is what blows my mind.

• 1:19:43Speaker 01

  Yeah, yeah, it's true. It's true. They're just acting like they're not a part of us.

• 1:19:48Speaker 03

  Right. Yeah, they're like, well, I mean, I'm just, I have this, this new trait, so.

• 1:19:54Speaker 01

  Yeah.

• 1:19:54Speaker 03

  Sorry.

• 1:19:55Speaker 01

  Sorry. Can't help it.

• 1:19:57Speaker 03

  It's better for me.

• 1:19:57Speaker 01

  Yeah.

• 1:19:58Speaker 03

  Yeah.

• 1:19:58Speaker 01

  It is so interesting. Well, next week we'll have a lot more for you, but if you want to read more, oh, boy.

• 1:20:05Speaker 03

  Oh, yeah, we do.

• 1:20:06Speaker 01

  We sure have a lot of sources.

• 1:20:07Speaker 03

  I always go first.

• 1:20:08Speaker 01

  You do, yeah, thanks.

• 1:20:09Speaker 03

  Just gesture to you. Okay, so the, the Cheating Cell by Athena Actipus, I thought it was absolutely fascinating.

• 1:20:17Speaker 01

  Love it.

• 1:20:17Speaker 03

  Great, great dive into evolution.

• 1:20:19Speaker 01

  And then I was like, oh, I think Erin is reading that, so I'm gonna not.

• 1:20:23Speaker 03

  Cause we're friends on Goodreads. Then there's a paper by Colin and Malley, Pedo's Paradox, Evolution's Prescription for Cancer Prevention from 2011. And then if you want to read sort of a nice little overview of adaptive therapy by Zhang et al. from 2023 in Critical Reviews in Oncology Hematology.

• 1:20:43Speaker 01

  Love it. I have a, a good number of papers for this episode. I think a couple to shout out, there's like three papers going from 2000 to 2022 by Hannah Han and Weinberg, and one is just by Hannah Han that are like called the hallmarks of cancer. So those are kind of like the classic.

• 1:20:59Speaker 03

  I have a few of those.

• 1:21:00Speaker 01

  Yeah. And then there's a couple that are like pushing back against the hallmarks of cancer, which like, I don't think changed things all that much, but I have a few of those as well, too.

• 1:21:08Speaker 03

  Catchy title, though.

• 1:21:09Speaker 01

  Yeah, they got, they got me. But, but some of them are good and they really just talk more about the microenvironment. So one of them that I particularly liked is Over a Century of Cancer Research: Inconvenient Truths and Promising Leads by Sonnyshein and Soto from 2020. But again, there's a bunch more. I don't even know which other ones to shout out. There's so, there's so many. Lots more on the mechanisms of carcinogenesis from environmental things. If you want that, you can find them all on our website.

• 1:21:36Speaker 03

  Yes.

• 1:21:36Speaker 01

  ThisPodcastWouldKillYou.com.

• 1:21:38Speaker 03

  It's truly a massive list. Happy reading. Happy reading, everyone.

• 1:21:41Speaker 01

  You're welcome. Everyone writing their term paper. It's like, thank you.

• 1:21:45Speaker 03

  I mean, seriously.

• 1:21:46Speaker 01

  Yeah, seriously, we did it for you. You're welcome.

• 1:21:48Speaker 03

  Yeah.

• 1:21:49Speaker 01

  Thank you.

• 1:21:50Speaker 03

  Thank you also to the providers of our firsthand accounts again. Yep. What can we say that hasn't already been said? Thank you from the bottom of my heart.

• 1:21:57Speaker 01

  It's, we can't thank you enough, is the truth of it. So, thank you, thank you, thank you, thank you.

• 1:22:02Speaker 03

  I'm gonna say thank you again to Blood Mobile, in addition to John and Brett for-

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  Yes. Those are our husbands. We thanked them before.

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  And Blood Mobile, my brother.

• 1:22:11Speaker 01

  Brother, for the music.

• 1:22:13Speaker 03

  For the music.

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  Yeah, we really appreciate you.

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  Yes, we do.

• 1:22:16Speaker 01

  Thank you to everyone here at the Exactly Right Studios.

• 1:22:19Speaker 03

  Thank you, thank you.

• 1:22:20Speaker 01

  Thank you to Tom and Leanna and Pete. Thank you to Jessica and Sabrina and Boomer. We're gonna thank everyone today. I remembered names.

• 1:22:27Speaker 03

  Oh, my gosh.

• 1:22:28Speaker 01

  We've got this.

• 1:22:30Speaker 03

  So many thanks to go around. Thank you to our listeners. Thank you to our patrons. You all make this possible.

• 1:22:36Speaker 01

  I hope you guys enjoyed this episode.

• 1:22:37Speaker 03

  Yeah.

• 1:22:38Speaker 01

  I did.

• 1:22:38Speaker 03

  Yeah.

• 1:22:39Speaker 01

  It's really-

• 1:22:40Speaker 03

  Tell us what you think.

• 1:22:41Speaker 01

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  And until next time, wash your hands.

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  You filthy animals.

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