This Podcast Will Kill You - Ep 203 Cancer Part 2: Why does it happen?

Episode Date: March 10, 2026

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/3WwtIAuSee omnystudio.com/listener for privacy information.

This is exactly right. Hello, it's me, Anna Sinfield, the host of The Girlfriends. I'm back with more one-off interviews with some truly kick-ass women on The Girlfriend's Spotlight. I'm going to climb this. Is Badness Hereditary? Let's see how we can stop killing. I'm not too intimidated by her. What are you talking about?

Listen to The Girlfriend Spotlight on the IHeart Radio app, Apple Podcast. podcast or wherever you get your podcasts. Back in 2016, we said, let's do a podcast. Little did we know it would last 10 years. I mean, but here's the thing. Stay out of the forest. You're in a cult. Call your dad.

This is terrible. Keep going. You guys stay sexy. Don't get murdered. Elvis, do you want a cookie? A cookie? My favorite murder turns 10 this month. Join us for new episodes every Thursday on the Exactly Right Network. Listen to my favorite murder on the IHeart Radio app.

Apple Podcasts or wherever you get your podcasts. Goodbye. Hey, it's Alec Baldwin. This season on my podcast, Here's the Thing. I talk to composer Mark Shaman. It's about the hang. It's the pleasure of hanging out

with the people that you're with. You know, Rob and I was always a great hang. And journalist Chris Whipple. Every White House staffer, they work in a bubble called the West Wing. And it's exponentially more so in the Trump White House. Listen to the new season. of Here's the Thing on the IHeart Radio app

or wherever you get your podcasts. 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. 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 in to 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 egg 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. 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. 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 of 15 months, but I've made it my mission to inform and encourage my friends and family members to get their colonoscopy. I was 45 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. 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 burgo 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 ringer this past year, from surgery to chemo to radiation now oral chemo. 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 breast. 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 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. 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. 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 first hand accounts are the backbone of this of this podcast. They bring so much that we couldn't that we could not. Yeah, they absolutely do. This podcast would not be the same without your first hand 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 first-hand 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. It does. Hi, I'm Erin Welsh. And I'm Erin Elman Updike. And this is, this podcast will kill you. Welcome to episode two of our series on cancer. It's a big one. It really is. If this is your first time tuning in to this series, go check out the first episode. Yeah. We've got four total common for you. 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. Right. Because in this episode on lung cancer, because I listen to the cancer series.

Exactly, exactly, exactly. Yeah. It gives us an opportunity to explore the big picture of what this all means. Right. What does that mean? How are these episodes organized? Great question. We'd love to tell you. 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? Right. Next episode, treatment.

That's a big one. I mean, that encompasses a lot. Yeah. And the last episode, the fourth and final, is all about screening, prevention, kind of understanding the landscape of cancer today and where we might go from here. Exactly. Exactly. Yeah. 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, Aaron, 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? So many opportunities to do that.

Yeah, yeah. 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 first-hand 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. To affect so much of our lives. 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 first-hand accounts have been so integral. So thank you again. Thank you. Thank you. They really do mean everything to us.

Yeah. Okay. one more piece of business. Last piece of business. Quarantini time. We're still doing it. We're still doing it. If you didn't hear last week, we are no longer doing alcohol in our quarantini recipes.

So you could consider them all placebo ritas, but we're going to call them quarantinis. It's just whatever strikes us. And this week we're drinking. The crab. The crab. It's an affigato. espresso, ice cream. Let's go get one after this.

Subscribe to our socials to, yeah, let's go get one. Subscribe to our socials to, uh, see how it's made. And check out our website where you can find all the other sorts of TPWKY related things. This podcast will kill you.com. Yeah. Check it out. Rate review and subscribe.

We're also on YouTube. And now. Now for the real stuff. The real stuff. Okay. Let us get in to the biology of cancer. Shall we? We shall after this short break.

Hi, it's Alec Baldwin. This season on my podcast, here's the third. thing I'm speaking with more artists, policymakers, and performers, my composer Mark Shaman. Once you've established that you have the talent, it's about the hang. It's the pleasure of hanging out

with the people that you're with. You know, Rob and I was always a great hang. We would sit in kibbets for hours and then eventually get around to the music. That's what I mostly think of when I think of him, the time together laughing. Lawyer at Robbie Kaplan. The great gift of being a lawyer

is the ability to actually change things in our society in a way that very few people can. I mean, you can really make a difference to causes in the United States if you bring the right case at the right time. Marriage equality. Yeah, Windsor's the perfect example. And journalist Chris Whipple. Every White House staffer, they work in a bubble called the West Wing, and it's exponentially more so in the Trump White House. Listen to the new season of Here's the Thing on the I Heart Radio app, or Wherever you get your podcasts.

Ever feel like you're being chased by the marriage police. Welcome to Boys and Girls, the podcast where dating isn't dating. Arranged marriage is basically a reality show, except the contestants are strangers and your entire family is judging. You're sipping coffee with one maybe, grabbing dinner with another, and praying your karmic Ken or Barbie appears before your shelf life runs out.

Trust me, I've been through this ancient and unshakable tradition. I jumped in, hoping to find love the right way, and instead I found chaos, cringe and comedy. And now, I'm looking for healing. Boys and Girls dives into every twist and turn of the arranged marriage carousel, the meat-awquard, the near-misses, the heartbreak, and let's not forget all the jokes. Listen to Boys and Girls on the I-Heart Radio app, Apple Podcasts,

or wherever you get your podcast. When you feel uncomfortable, what do you put on? Biggie. You put on Biggie when you feel uncomfortable? Because I want to get confident. This is DJ Hester Prynne's Music is Therapy, a new podcast from me, a DJ and licensed therapist that asks one simple question. Who do you want to be? And what's the song that can take you there.

Music changes what you feel. And what you feel changes what you do, right? That moment where a song shifts something inside you, that's where transformation starts. This year I'm talking to experts across every area of life, like personal finance icon Gene Chatsky, New York Times journalist David Gellis, relationship legend Dan Savage, human connection teacher Mark Groves,

and the man who sheet my ear more than anyone, Questlove. They'll bring the strategies. I'll pair them with the right records and will teach you how to use the music to make change stick. This isn't just a podcast. It's unconventional therapy for your entire year. Listen to DJ Hester Prins Music is Therapy on the IHeart Radio Act.

Apple Podcasts or wherever you get your podcasts. On August 28th, 2025, I got a call for 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 he 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 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, 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 50s and 60s. I was 31, 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 rutoxinib, 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 20 to 30 injections per session. 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 flying, 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 reoccurrence and something I may live with

long term. While I'm grateful for an overall favourable prognosis, the experience permanently changed how I think about my health and my relationship with my body. When I was 32 in 2016, I was diagnosed with breast cancer. I found a lump in the shower, went to my local doctor and within 10 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 DEP 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 2025, 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. 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 and I find 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'd 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 ribocycly, 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 scams have showed. I know some people have been on this drug for eight to ten 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. So I actually want to start this week's episode exactly where I started last week's episode. Not where I ended it, but where I started it, which is with the definition of cancer. Okay. Which is the logical place to start.

Yeah, yeah, yeah. Yeah, sure. So I'll go back to that National Cancer Institute definition. Great. 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? I've built Legos.

Okay. But I don't know if I ever had a kit. Okay. So if you have ever built, if anyone listening and watching has built. to 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 going to need to follow the specific instructions that come in that Lego box. I mean, I've built many IKEA pieces of furniture. Is that the same kind of thing? Okay, great, great, great. Very similar idea. Just more pieces,

etc. Perfect. 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 four by four squares or whatever. Oh my gosh. Yeah. 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. I kind of, I have to admit, I love putting together IKEA furnisher.

You would love a Lego kit then. I'm sure that I would. 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. Oh, yeah. Because if every cell in our body just divided nonstop, it would be madness. It would be a problem. We wouldn't be here in short. Yeah. So we have sets of instructions that are encoded into our DNA, which have patterns, instructions that our cells are going to use to make the right types of tissue in the right types of places 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.

It's like instructions on instructions. Exactly. You will grow and replicate. But not only that, you're going to become this specific type of cell and this specific type of organ in this specific little bit. And then you're going to forget how to do all those other things that you used to be able to do. Yeah. 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 are current. in the process of cell replication. So we have a lot of checkpoints in what is called our cell 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. No. Even though they came from the same place. Right. 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. 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, Aaron, they also leverage these rules in a way that benefits them and not us. So I'm excited about this. 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 at. actually the right time to divide. Right. 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, Aaron, in a lot of cancers, are what are called oncogene mutations. Yes. 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. 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 at 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. Gas pedal to the floor. 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. Yep. 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. Right. Stop, done, destruct. 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. Yep. And a lot of the genes involved in this process, we call tumor suppressor genes. Right. And in cancer, these mechanisms are turned off. Yep. That's the get, take out the break of the car. The break is broken.

It's completely gone. Yeah. 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 think we'll be able to connect it back. Yeah. It's BRCA. Oh, okay. Okay. You gave me a face like it was going to be something different. I don't know. It will be something different, the face that you're making. Yes, yes, yes. Yeah. But BRCA 1 and Brecate 2, 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 Bracca 1 or Bracca 2, 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. But there is another classic tumor suppressor that I feel obligated to talk about because it is, is its function is affected in almost every case of cancer.

And that is TP53. That's what I thought you were going to talk about. Yeah, that's what I figured. What proportion of cancers? Well, okay, 50% of cancers have a mutation in this specific gene, TP53. Yes. 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. Right. You're too hard to keep an eye on. Exactly. It's enough. 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, the protein can't do its job anymore. So this particular gene is really important in cancer formation. It's a big deal. 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 Leifromani syndrome. Next week's book club episode. Oh, amazing.

Yes. Oh, so definitely listen to that one. And that you are prone to a wide variety of cancers with Leiframine 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 upregulate. 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 dilatirious 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. Right. Override, override, override. Override. We also see that cancer cells alter how they do metabolism. Yeah, they do. 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. Of course. And to get blood, you need blood vessels because that's where our blood happens to be contained. So cancerous tumors upregulate the process of angiogenesis, which is the formation of blood vessels. So they make their own blood vessels in order to feed themselves. 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. Yeah. 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. Yeah, we can do whatever, take whatever form. 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. The ecology of a tumor. The ecology of a tumor. They have really big impacts on things like our inflammatory system. Yeah.

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. Yeah. 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. Yes. 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. Mm-hmm.

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.

It's a disease of what we call G by E, or genetic and environmental interactions. Right. So the mutations that we know are associated with cancer are a necessary but not sufficient part of cancer. cancer biology. Right. A cancerous cell doesn't turn cancer simply because it has one mutation. 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, Aaron, but that some of, especially 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. Right. 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 exposure is that we don't fully understand the direct links how those might be playing a role. 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. Exactly. Exactly. 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 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. It's a perfect storm, but it's storming all the time. 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. Right. The pathway is different. Different. The progression is different. The mutations might be different. That, you know, nutrient, whatever, everything is different. 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.

Yeah. Why isn't this treatment working exactly the same? Yep. Right. So really cancer is, I'm really wanting you to start talking, Aaron, because cancer is kind of our cells forgetting how to function as a multicellular organism. Yeah. 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. But they also do cooperate within a tumor. Ooh, I can't wait for you to tell me all about that, Aaron. And they do. And they cooperate with that particular environment.

Right. And they make it very conducive for themselves and themselves only. And they're leveraging our body systems in order to do this. So, Aaron, 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. It's so funny that you said shed some light because I literally say something just like that. I can't wait. Hi, it's Alec Baldwin this season on my podcast. Here's the thing I'm speaking with more artists, policymakers, and performers by composer Mark Schaman. Once you've established that you have the talent, it's about the hang.

It's the pleasure of hanging out with the people that you're with. You know, Rob and I was always a great hang. We would sit in kibbits for hours and then eventually get around to the music. That's what I mostly think of when I think of him, the time together laughing. Lawyer at Robbie Kaplan. The great gift of being a lawyer is the ability to actually change things in our society in a way that very few people can. I mean, you can really make a difference.

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Ever feel like you're being chased by the marriage police? Welcome to boys and girls, the podcast where dating isn't dating. Arranged marriage is basically a reality show, except the contestants are strangers and your entire family is judging. You're sipping coffee with one maybe, grabbing dinner with another, and praying your karmic ken or Barbie appears before your shelf life runs out. Trust me, I've been through this ancient and unshakable tradition. I jumped in hoping to find love the right way,

and instead I found chaos, cringe, and comedy. And now I'm looking for healing. Boys and Girls dives into every twist and turn of the arranged marriage carousel, the meat-awquard, the near-misses, the heartbreak, and let's not forget all the jokes. Listen to Boys and Girls on the I-Heart Radio app, Apple Podcasts, or wherever you get your podcasts. 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 Braco 1 positive. With the Bracogene, 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. 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. 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. 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 their careers on hold, who have to care give full-time, while also making sure their school-age children's 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. 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.

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 of millions who have also participated in finding this cure, we still struggle to effectively treat or prevent or even define this disease. Yeah. Why? Why? To answer that, we have to rethink cancer from an entirely different perspective.

Rather than seeing cancer as the 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, Aaron, 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?

Wow. Why is cancer so common in humans? Shouldn't we have evolved to resist it? It just doesn't make. sense. I mean, does it, though? Then again. Paraphrasing Theodosius Dobjansky, 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 Dobjanski's essay. Yeah. So let's shine that evolutionary light on cancer. This is a story told in four parts. 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. The third scans for patterns across the animal kingdom in cancer resistance and susceptibility. And the fourth and final part asks, how can we apply this evolutionary knowledge to design better strategies for cancer treatment today? Oh, Erin. 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.

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. 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. It could not exist. 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. Yeah, it works pretty well. 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, so unique.

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. Possibly more than our human cells. Possibly. This cooperation is really quite astounding. you think about it. In her book, The Cheating Cell, researcher Athena Ectypest presents what she calls the multicellularity playbook. I like this in contrast to, like think about this in contrast to the hallmarks. Okay. Yeah, yeah. Cancer hallmarks. Right, right. Right. Right. Number one,

don't divide out of control. Number two, self-destruct if you're a threat. Yeah. Number three, share and transport resources. Number four, do your job, division of labor. Yeah. Number five, take care of the environment. Oh. If only we could all. Basically, just, I know. Follow the rules of multicellularity. I mean, listen.

Just too much we could even go into there. But basically it comes down to do your job, be respectful, and everything's going to be hunky-dory. We're all going to be chill and living together. It's great. Clean your dishes out of the sink, put them in the dishwasher. Is it that hard? Just pick up after yourself. Yeah.

And of course, we know that things don't always go that way. No, they don't. 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.

in this process involves copying the DNA within ourselves. With all that copying, a few errors are bound to slip in there. 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. Maybe the mistakes are harmless. Maybe they're repaired. Or maybe the mistakes are too big and the cell is earmarked for destruction. Exactly.

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 break out of commission. In no time, that cell becomes two, then four, then eight, then 16, and so on. That's how cell division works. 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. 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. They are just growing because they can grow. Yeah. Yep. Yep. That's it. And spread. And spread. Yeah. Because they can. It's because the mutations evolve. And so ultimately, if this proliferation continues unchecked, it will result in the death of the entire organism, which includes the cancer cells themselves. Which is a bad thing. Right.

So we've got these cancer cells outcompeting normal cells. But if that ultimately kills the organism, how can that be evolution? Like, isn't that just a dead end? It is for that individual cancer, which will go extinct when its host dies. Extinction is not a new concept. And this is also asterisk for if you're transmissible cancer, another story. Right. That's a whole other story. But like dinosaurs have gone extinct. Yeah. Humans have killed off many different species in the past. We have made go extinct. You know how many thousands of years. Yeah. It's part of the process of evolution. 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. Yes. Yes. So to quote from Ectypice is 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 apart, end quote. It's just evolution. It's just evolution. And we're not saying that to minimize it. No. 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. But, I mean, even parasites are just evolution. Yeah, exactly.

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. They're surviving. That is all they are doing. And the ones that do survive are the ones that have the right characteristics.

The right tools, the right characteristics. In that particular environment. That is that environment at that time. Yeah. Yeah. And evolution is working on that population of cells. Right. So because cancer is not a one-time event.

No. 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 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 does. 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. It is instead an evolving dynamic mass of genetically diverse cells. 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. And again, these cancer cells, they're not replicating uncontrollably or evolving resistance because they're evil or want to. to succeed. Or they're trying to kill you. They have simply inherited the instructions to do so. Part two. Okay. Defense against cancer. 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 are normal cooperative cells already possess. 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 tract or skin, proliferation, differentiation, movement, and resource utilization, these are what makes us multicellular organisms. 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 talk about the placenta. 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? And it's sometimes hard to strike. Yeah. And so there's this thought that like cancer is one of the costs of higher fertility. Oh, that's so interesting. Because there's more tolerance for things that are like you but not quite like you. Yeah. Just a little off. Oh, that's super interesting. Right. It's a tightrope. Yeah. So if these processes are allowed to continue unchecked, though, cancer might be the outcome. So it's either you are a whole, you know, too tight of a control over them. And then you put stagnation.

Right. and under development or not enough control. And then you end up with cancer. Yeah. Oh, that's so interesting. Yeah. This is the crux of cancer. The constant tightrope walk that we do as organisms to balance chaotic growth with stagnation.

As Ectippus puts it, quote, this leads to the counterintuitive conclusion that the optimal level of cancer risk for an organism is not zero. Right. Yeah. That is, to me, that's like the bottom. line of everything. Yeah. That cancer is the consequence of multicellular life for growth and division reproduction. Right. It's all of the things that we already do. It's just doing too much. 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 decision is made. There's no

conscious thought here. Just using it as a shortcut. Can the cell be repaired? Right. Should we shut down replication until the error is fixed? Should the cell self-destruct? This is where something like TP-53 comes in, our famous tumor suppressor gene, also known as the guardian of the genome, which I really love. I know. I just think it sounds so noble. I know. So TP-53 takes in all this information and it initiates the appropriate response. And that's just one example 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's just like that. What's that? Who's coming? Everyone's using.

Next door. Yeah. It's just, it is just like that. And so for the most part, our cells are quite sensitive to self-destruction. You just give them a funny look and they're like, okay, fine, I guess I'll just self-destruct. They're committed to cooperation. And so often 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.

You're not really pulling your weight, man. Right. Like they want constant positive reinforcement. Yeah. And so if their neighbor cells, like, I'm just, it's not doing it for me. It's not me. It's not me. It's you. Right. Then they're like, okay, I guess I'll just self-destruct. Yeah. And the neighbor cells will eventually be like, you need to self-destruct. 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 neighbors are keeping a watch on them. And then there's this more global line of defense, the immune system. 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. 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,

that 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. Exactly. 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. No, yeah. I saw 30 to 40. Yeah. Yeah. It's bananas. And I was like, it is also brilliant to write this paper. You will be cited so frequently because everyone's going to be like, how many cells are in the body?

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. Seriously. And like, if you really know how many times we make mistakes in DNA replication, it is fascinating that it doesn't, that cancers and other deleterious mutations don't arise more frequently. Right. I mean, and this is a reflection of millions of years of evolution, billions.

When we look at an age distribution of cancer diagnoses, most happen later in life. And comparatively few happen in childhood, despite childhood being a time of rapid cell proliferation and differentiation as we grow and mature. There is stronger selection for those cancer suppression mechanisms at an early age 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.

To our whole organism. To our whole organism, yes. And remember, again, it's a tightrope. These defense mechanisms don't always function perfectly because there's a tradeoff 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. Same with wound healing. Same with tissue repair, making new blood cells and so on. How do different species balance this tradeoff, like what patterns exist? Part three. Okay. Cancer across the animal kingdom. Okay. There are cancerous growths in plants and fungi. I'm not going to talk about them. They're so interesting and cool looking now. They're very cool, but it's that's too big for. Oh, yeah. This is already too big. Yeah, I know, I know. But it is true. It's all multicellular organisms and that. It includes plants. Yeah, yeah.

Almost all. I read some stuff about sponges that I took out. But anyway. Sponges, though. They just sort of like pinch it off and they're like, you don't need anymore. Yeah, yeah. That's cool. Kind of like what our guts do a little bit.

It's very cool. Yeah. So knowing what we know about cancers, what are some patterns we think we might find. 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. And not everything else, yeah.

But you know what I mean. You still need the initial. You need that. You need the potential. Yes. Yeah. So you might expect that the more cells there are, the greater the risk of cancer. Do we see that, Aaron?

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 like shrews and hedgehogs. That's not what we find.

Interesting. Yes. In fact, there seems to be no correlation at all between longevity, body size, and cancer across species. Huh. So this surprising finding has a name. It's called Pito's Paradox. Oh, I've heard of this.

Yeah, yeah, I know Pito's Paradox. Pito's Paradox. So elephants, despite having 100 times the amount of cells that humans do, do not have 100 times the risk of cancer. Yeah. In fact, elephants are less likely to develop cancer compared to humans. Interesting. On the other end of the scale, mice are more likely to develop cancer than humans are.

Really? Really. No one talks about that. I know. just the mice we grow in labs, I presume. 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 Pito's paradox and the observations that have been used to formulate it.

Anyway. 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 species. Okay. Yeah.

How interesting. Yeah. So why might this pattern not hold across species? You got to have, they got to have something else going on. There's got to, I mean, there's. Some other protective mechanisms. 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 TP 53 compared to humans, two copies. I learned that one. Yeah. I knew that one. Obviously forgot it, but I learned that one. It's, we blew my mind. Yeah. Yeah. Yeah. Yeah. Yeah. There, maybe the, there's species immune systems could be more tuned into 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. So it's like tumor infighting kind of the thing. Like there's something about like, yeah. Just then the way that it interacts with their immune system is going to be different. Something like that, yeah. Interesting.

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. Pito'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 want to 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. Oh, interesting. Because they're like, make more eggs.

Make more. Proliferate, proliferate, proliferate. And elephants, which mature later on, might invest more in cellular watchfulness earlier in life. Interesting. Just to make sure that they survive to reproductive age. Right. Of course. So Pito's 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. Beyond Pito's 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 potentially cancer-causing pathogens found in raw meat. Interesting. Okay. Cool, cool. 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 involves making big things. And species that have undergone a genetic bottleneck like the Santa Catalina Island foxes tend to have higher rates of cancer. Prevance for them is greater than 50%. Really? So that suggests that genetic diversity, especially when it comes to immune diversity, is really important when it comes to being protective against cancer. 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. No, no, no.

And like just the diversity already that you've said. Oh, there's, yeah. I know. I know. I know. You know the internet. I know the internet. I'm familiar.

You've heard of it? I've heard of it. We're quite close. 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 against it. Defense is against that kind. Yeah, yeah. 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. Because again, the immune

system mechanisms and the inflammatory process and the wound healing process uses a lot of those same features that cancers exploit kind of a thing. Yep. Yep. Yep. And this is, by no means an exhaustive list of the patterns that we see in cancer risk across the animal kingdom. Yeah. 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. From an evolutionary perspective. From an evolutionary perspective when it comes to proliferation and differentiation. Right. But 40% might also reflect an evolution. 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. Things like cigarettes, processed meats,

our sedentary lifestyles, our increased longevity, all of these things lead to a higher risk of cancer. Alcohol. Alcohol. And correspondingly, they lead to a need for a better approach to treatment. Part four. Okay. 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. In the context of evolution, Aaron.

In the context of evolution. It's the same old story, right? 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 from other fields outside of cancer. Cancer. Like agriculture. Okay. To devise ways to minimize the emergence of resistance in the first place.

Okay. One approach called adaptive therapy is modeled after integrated pest management. Integrated pest management? Yeah. Yeah. Which is an agricultural... What a throwback. 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 blast 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. 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. Right. You're just like, okay, how do we get to 72? You're not trying to get rid of anything. You're just trying to not let it get any bigger. Yeah. And sometimes maybe getting rid of something means getting your immune system to step in. Sometimes it means just like slowing things down. Right. 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 out-competed by sensitive ones. I came across a great analogy

explaining this that I really like. So think about like a big, bulky umbrella. Okay. So this is our resistance mechanism. Okay. It's heavy. It's annoying. You have to lug it around everywhere with you. Always forget it. Always forget it. But if it's raining all the time, time, i.e. big doses of chemotherapy, the inconvenience is totally worth it. And you're probably not going to want to leave it somewhere. Yeah. But if it's mostly sunny or just occasional drizzles, you're like, you're going to forget at a cafe and not think about it again. I'm going to just wear my raincoat. Right. It's going to be fine. And so resistance can also like you can, cells can also evolve to no longer be resistant if there's not that pressure to maintain resistance.

So the beauty of adaptive therapy is that it's both generalizable and personal. Right. You 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. And it could be with any drug, right? Any drug that initially shows a benefit you could do it with. You could do that way. So, sounds great in theory. Is there any clinical evidence to back it up?

Tell me. There is. The first clinical trial testing adaptive therapy was conducted 10 years ago in 2016 on people with metastatic processes. state cancer whose cancer was no longer responding to hormone therapy. Those who received adaptive therapy had a median time to progression of 27 months compared to the 16 and a half months time to progression with standard treatment. So that's an extra 11 months, 10 months, 11 months. That's huge. Huge. Huge. So it slowed tumor growth in that way. 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. Right? Some cancers are going to respond better to some therapies than others. And researchers have devised different criteria for determining when a cancer might be treated with an aggressive versus an adaptive approach. Like when what is going to result in the outcome that we most want or like the ideal outcome. 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? cross 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. Yeah. But resistant cells, so they've, there are some resistance that, 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. 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.

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 going to kill me. It's going to kill me. I'm going to pump it out, pump it out. 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. So interesting. Exhaust them. So it's not, 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. So 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. And radiation. And so there's this

idea that like maybe maintaining that tumor, and again, this is very dependent upon the individual of 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. Keep it how it is. Yeah. Yeah. Just don't let it do its invasion thing. Yeah. Yeah. Or what if we directed evolutions 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, this is sort of the idea. Yeah. 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. One percent 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? Oh, this is so true, Erin. So stay tuned for next week when we

talk about cancer treatment. Another great cliffhanger. Thank you. Thank you. What a journey, Aaron. I just, it really helped me to think of cancer cells as just success. in an evolutionary context using the tools that they already had in our normal cells. Which I honestly still, like that is why they seem like a population of bacteria to me. But like, but they're not. I know. I know. Because they're us. But it's us. So they have all of our traits and all of this. Bacterial cells have, you know, certain toxins or certain whatever. They have other things that they, and we don't. Right. And they're, they don't. The cancer cells are working with the toolkit. Yeah.

That every single one of our cells already has. And that is what blows my mind. Yeah. Yeah. It's true. It's true. They're just acting like they're not a part of us. Right. Yeah. They're like, well, I mean, I'm just, I have this new trait. So, sorry. Sorry. It's better. It's better for me. Yeah. Yeah. It is so interesting. Well, next week we'll have a lot more for you. But if you want to read more, who boy. Oh, yeah, we do. We sure have a lot of sources. I guess I always go first. You do. Yeah. Thanks. Just gesture to you. Okay, so the cheating cell by Athena Ectypice, I thought it was absolutely fascinating. Love it. Great dive into revolution. I almost read that, and then I was like, oh, I think Erin is reading us, so I'm going to not. It's because we're friends on good readers.

Then there's a paper by Colin and Mali, Pito'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 Zang at all from 2020. 23 in critical reviews in oncology hematology. Love it. I have 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 Hanahan and Weinberg, and one is just by Hanahan that are like called the hallmarks of cancer.

So those are kind of like the classic. I have a few of those. Yeah. And then there's a couple that are like pushing back against the hallmarks of cancer, which like, I don't think change things all that much, but I have a few of those as well too. Catchy title, though. Yeah, they got me. 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 Sonasine 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 many. Lots more on the mechanisms of carcinogenesis from environmental things. If you want that, you can find them all on our website. Yes.

This podcast will kill you.com. It's truly a massive. list. Happy reading. Happy reading everyone. You're welcome. Everyone writing their term paper. It's like, thank you. I mean, seriously, though. Yes, seriously. We did it for you. You're welcome. Yeah. Thank you. Thank you. Thank you also to the providers of our first hand accounts again. Yeah. What can we say that hasn't already been said. Thank you from the bottom of our hearts. We can't thank you enough is the truth of it. So thank you. Thank you. Thank you. Thank you. Thank you. I'm going to say thank you again to Bloodmobile in addition to John and Brett for. Yes.

Those are our husbands. We thanked them. And Bloodmobile, my brother. For the music. For the music. Yeah, we really appreciate you. Yes, we do. Thank you to everyone here at the Exactly Right Studios. Thank you, thank you.

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