SIO523: What Cancer Actually Is, Part 1 (with Dr. Eric Jaffe)

Transcript

This transcript was generated automatically and may contain errors — the audio is the record.

0:00:12 Thomas: Hello, and welcome to Serious Inquiries Only. This is episode 523. I'm Thomas Smith, and I know I say this all the time, but I am so excited for these episodes. Dr. Eric Jaffe, who listeners will know and love, biology teacher and sayer of weirdly named thingies in biology that I don't totally understand, that are sometimes named after, like, cartoon characters. I don't - I don't get it. I don't get what they're doing. It seems weird, but it's what it is. Anyway, Eric is going to be teaching us about cancer, and we've got two amazing episodes. In part one here, Eric's going to Be teaching us all about what cancer is, essentially, broadly speaking. And in part two, we're going to cure cancer. Eric's gonna tell us about how we fight cancer, why there aren't necessarily cures, all that stuff. I learned so much. Seriously, I'm so thankful to Eric for doing this. You're going To learn a ton. At times, it's the usual thing with Dr. Eric Jaffe where we're getting a bit of a biology lecture. It can be a handful, but stick with it because by the end, Eric has always found a really cool and creative way to make sure that we all are following along. And so without further ado, I want to get to part one of this cancer duo here in which we're going to learn all about it. It's so interesting and different than I kind of thought it was. Having been fortunate enough not to have dealt with cancer intimately myself or any like immediate family members, I know it's going to be much different for many people listening. Either way, I hope you'll get a lot out of it. And if you'd like that part two right away, go to patreon.com/seriouspod. It's already done. It's there. For normies, it'll be out in a couple of days or something. All right. Without further ado, let's get on over to Dr. Eric Jaffe and let's learn about cancer.

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0:02:10 Thomas: And welcome back to the show, Dr. Jaffe. How are you doing today?

0:02:13 Eric: I'm doing well. It's summer break, it's super hot, and my dog just started physical therapy.

0:02:17 Thomas: Today just gonna ask dog news dog update

0:02:21 Eric: The dog news is, now you know this, I am a tiny human being and my dog is 85 pounds and trying to teach him physical therapy exercises is a lot right now because he is very, very energetic and overexcitable. The good news is it both tires him out physically and mentally, so even though it's about 100 degrees in Philly right now, he's currently passed out on the bed.

0:02:34 Thomas: Yeah that does sound geez oh 100 degrees holy moly yeah I wonder if uh maybe that climate change thing is maybe there's something to that I don't know we'll have to see too early to

0:02:48 Eric: Yeah, it has been hot the last couple days.

0:02:56 Eric: More importantly, Jermaine to the topic we're going to be talking about today. Definitely a good idea to wear sunscreen if you're out in the sun.

0:03:02 Thomas: Know oh yes good transition what are we going to be talking about today Hmm.

0:03:06 Eric: We're gonna be talking about cancer today. And so like, I like to have all of my episodes have kind of like a one to two sentence tagline that kind of frames and structures it. And this one is basically following the theme of biology is all about context, and what the context of cancer is, why it develops, and then why I always get frustrated when people have conspiracy theories about like, the cure for cancer, in quotation marks, right? Because there's not one cure for Cancer, as we'll see, although we will talk about some technologies at the end that are adaptable and kind of multifaceted to be able to fit multiple types of cancer. That's kind of the overall plan for today.

0:03:45 Thomas: They already have cured it, but they don't want us to have the cure because that's how it works. Who would ever want to get all the adulation and Nobel Prizes and money in the world for curing cancer?

0:03:57 Eric: Not only that, like, I think this is important to estate with all of the distrust we have for biomedical research lately, but I share your frustrations with the business models of pharmacological companies, right? Like big pharma is a thing. There is a profit motive in that sphere that is very unhelpful. But remember that most of this stuff is based on nonprofit research done by academic labs that receive government grants.

0:04:20 Eric: And so if you're going to really talk about like big pharma is scare quotes, you're You're also going to have to find a way to square the fact that they are using publicly available research that you can look up and validate for yourself. And that's kind of one way this conspiracy theory always falls apart is I rotated in a breast cancer research lab. They did not receive any money from pharmacy companies, right? They just got their NIH and NSF funding to do the basic research that then pharmacy companies will take that last like five to 10 % of the way into drug development and treatment.

0:04:55 Thomas: Wow. I didn't even know that's how it worked.

0:04:57 Eric: This goes for vaccines. This goes for cancer research. The underpinnings of all this stuff usually happens at the basic research level that then translates. So, for instance, I was a developmental biologist, and most of my grants, when I would apply for things, would show up as within the first two sentences, grainy head like three, which is the protein I studied.

0:05:17 Thomas: Here we go again.

0:05:19 Eric: Oh, we will have some fun names. But, like, I would almost always say grainy head like 3 is implicated in cancer because governments are just as interested in cures for cancer as the rest of the world. And so that's a really good way to kind of privilege your study for funding is by tying it back to cancer research. But I did not work for, you know, big pharma. I did not receive any money from them. I was not thinking about the effect my research would have on cancer treatment development. All I was thinking about was how do the cellular cables called actin sew together stuff during neural tube closure, which we can save for a future episode.

0:05:52 Thomas: So are you saying that like the whole thing about how, well, we have to let them profit from it because that's the only reason they'll spend the money to do the research? Like, is that kind of bullshit? Okay.

0:06:02 Eric: It's not bullshit entirely. It's oversimplified, right? Because there is a reason why a lot of the breakthroughs come from American companies, right, because that final 10 % of optimizing and mass producing and doing all that stuff that finishes it is super, super important. It just built on the shoulders of giants from basic research. And so like, you have to first disprove the basic foundational principles, similar to vaccine research, right. If you're going to talk about vaccines and say it's all a plot from Big Pharma, you have to tell me what part of germ theory you disagree with first. Before we get too deep in cancer, though, I did want to bring up something from the last episode because I've mentioned this from pretty much the first episode, but my expertise is a nested hierarchy like everyone else's, and that means that I'm not going to be infallible at everything. And a good example of this actually came up in the last episode when I was talking about sex and gender, because I was coming from a slightly mistaken idea of the more sociological context of gender, where it's more about the way that it interacts with society. But my good friend who's a emergency room doctor, kind of a real life Dr. Robbie, reminded me that they actually use gender in the physiological sense in the examination room and in the ER, and that you don't want to erase the real physiological aspects of gender and smush it into sex.

0:07:24 Eric: And so what I would say is my overall point still doesn't change that much because all it really means is that there's no reason to privilege biological sex over biological gender. One of them is not biological and the other sociological. It still means that both of them are biological. But this does kind of further feed into my point that the facts are what's true. The definitions are what you can quibble over and they're contextual.

0:07:46 Thomas: Okay. Yeah. I don't know that I totally remember what the difference would be with what you said.

0:07:52 Eric: Yeah, I basically said that gender is like the self -conception, how it interfaces with society, and that the biological sex is just as much your brain as it is the gonads. It turns out the biological basis of gender is the brain, and I still stand by the fact that there's no reason to privilege the gonad over the brain. But now it just means that there is no reason to privilege sex over gender when determining biological basis male and female.

0:08:15 Thomas: Okay, well let's dig into cancer, shall we?

0:08:18 Eric: Yeah, you know, no one has done it before. So I'm happy to be the first one to ever sink my teeth into this. Right.

0:08:23 Thomas: We're going to solve it here.

0:08:25 Eric: That is the theme is why don't we have a solve for cancer. And it's because it's extraordinarily complex. And because all that cancer is, is when cells kind of do what they're supposed to be doing in normal developmental context in adult tissue, right? Right? Similar to it's fine to behave like a college kid when you're 21. If you're behaving like a college kid when you're 43 and have a family, you're going to get a different set of side eyes, right?

0:08:50 Thomas: It's a good warning to give me right now as I'm almost 40.

0:08:55 Eric: I mean, I'm 37 and have no family.

0:08:58 Thomas: So you get to do it. You get to be cancer.

0:09:00 Eric: So I've got the one hit in the two hit hypothesis that we'll talk about in a couple minutes. But let's talk about what cells normally do. And I'm sure many of you have heard of this, but cells have a growth cycle called the cell cycle. And that's where you learn about prophase, metaphase, telophase, anaphase in high school when you talk about mitosis. You also learn about interphase. And this model that we teach in high school, or that we used to, we now have adapted it fairly significantly, kind of undersells that most of what happens in biology happens in that interphase, most of the time your cells are not dividing, they're doing what we call the G1 stage of the cell cycle. And that's your normal cell functions. The organelles are going to process nutrients. You're going to do your metabolism. You're gonna grow. Youre gonna do all that stuff. Once you get signals from these types of proteins called cyclins and kinases, you can think of these as like the carny in the carnival ride that is your cell cycle, right? They're the ones that start and stop the ride, make sure everything is ready to go to the next step. They're the checkpoints, right? And once you hit a certain checkpoint, you then move on to S phase. Now, S phase stands for synthesis. And this is when your DNA gets copied. Because if you're going to go from one cell to two cells, you need to have an extra copy of your DNA. And every time your DNA get copied, you introduce the risk of mutation, an unfaithful copying of the DNA. So your cells will once again pause here, make sure that everything was done correctly before moving on to mitosis in a stage that we call G2. G2 is like that final step where the cells have already copied their DNA. And now you've got the like ride worker that's going and checking the shoulder harnesses on the roller coaster before giving the go ahead to

0:10:47 Eric: Send the rollercoaster on the ride. Once that division happens and the cells are now either their growth or their repair, because typically cells divide when we need to grow new things or repair damaged things. They then enter a stage that's called senescence. And cellular senesence is the settling down of cells, right? It's when they, what we call differentiate, they stop being stem -like and start doing the thing they're supposed to be doing. Your skin cell starts taking on the properties of skin. Your stomach cells start taking on on the properties of stomach, right?

0:11:18 Eric: But they come from those stem cell populations that are dividing. Once they differentiate and become those cells, their divisions become much less frequent and their behaviors change drastically. They're really only going to divide when tissues are in need of repair or when there's specific signals being done. But they have now fundamentally changed their behavior. And more importantly, they've changed their properties, right, because we talked about how the reason why your genes matter is they form proteins which give of your cells traits. Once cells enter senescence, also known as G0, because they've kind of exited that G1, S, G2, M phase of the cell cycle. Once they're in that senesence, that G0. Now they have taken on those proteins that mark the functions that they're going to be doing in that adult tissue. And they really start to quiet down and they don't divide nearly as often. Make sense so far?

0:11:18 Thomas: I think so.

0:12:11 Eric: What cancer is, is cancer is all of the carnival ride workers are now out to lunch, right? Something happened where they're no longer able to do their job properly. And the roller coaster will keep going and going even if the other ride hasn't finished yet. And what will end up happening is you get a pileup. That pileup is what we recognize as a tumor. Because a lot of times a big key that tells cells to stop dividing, especially because they're used in repair. If I get a cut in my skin, there is now a gap between the set of cells on one side of that cut and the a set of cells on the other side of the cut, right? So they will fill in knowing that they're not in contact with other cells on that side, going towards that gap until they run into cells from the other site. Once they fill in cells at the other slide, they now know that the tissue is fully filled up. There's no space to go.

0:13:04 Eric: That's called contact inhibition. And that tells the cells to stop dividing. But if you're cancer, you have no chill when it comes to dividing. So you're going to keep dividing even though there's no space to go. And that three dimensional pile up is what we recognize as tumors. Yeah.

0:13:19 Thomas: It sounds so harmless when you put it that way, in a weird way, where it's like, well, I just got some extra skin, some extra something. Yeah.

0:13:28 Eric: And you would think that that's bad, but you don't really see how this can be the catastrophic life ending illness that it is for many people yet. Right. That's kind of the extreme oversimplification of cancer. Cancer. But cancer really has a couple of things that are hallmarks of cancer. And I think as we go through some of these hallmarks, you'll start to realize why they become kind of really harmful for the rest of the cell. So the first is, as I just mentioned, they're self -sufficient in their growth, right? They get these change in the proteins on the outside of the cells that do things like ignore that contact inhibition. They're also going to change the signaling pathways pathways that interact with other molecules in the tissue, right? Their behavior is going to look more like stem cells than they are like adult tissue. But your cells differentiate into those adult tissues to perform functions. So if you're losing the properties of that adult tissue, by definition, those cells are not going to be as functional in the organ they are now situated in.

0:14:29 Eric: So that's one problem is that they lose their ability to function like normal cells because they pick up those extra mutations, those things that change their properties, and they start looking and behaving different. Because in biology, form follows function. And once you start changing the form, the structure of the proteins, the shape of the cell, the place it's situated in, you drastically change its function. And so those cells start working less and less optimally for that organ.

0:14:56 Thomas: Are you saying it's not just like, oh, I've got a little like, you know, ball of stuff that shouldn't be there. It's like the other stuff around it is going to think that's the normal stuff. And then your other cells are going to like do the wrong thing because of the cancer cells.

0:15:12 Eric: It's more that your cancer cells are going to do more and more wrong things. But because now you're getting more and more of those cells, the nutrients, the space, the resources are now going to those cancer cells instead of to your healthy and functioning cells. There's also just straight kind of what we call steric hindrance, right? If I have a huge clog in my drain, my drain can no longer function as a drain. So a couple of ways that they become self -sufficient in growth is that they become insensitive to anti -growth signals. Because the same way we have kind of proteins called cyclins and kinases that promote the cell cycle. We also have ones that go, slow your roll, our DNA is damaged. Slow your roll. We already have contact with cells on the other side. And they just blow past these, but that also means that they're not checking for increased DNA damage. So they keep on kind of exploiting this, but they become more and more and more different over time. And we'll talk about one of the ways that that's really pernicious in a couple of minutes. So we have these cells that are growing a lot. They're resistant to anti -growth signals, and they're also resistant to what we call apoptosis. Have you ever heard of apoptoses before?

0:15:26 Thomas: Oh, I don't think so.

0:16:22 Eric: Now that is a sinister sounding word for something that is both sinister but extremely important and healthy part of the cell cycle. If mitosis, cell division, is the pencil that draws in structures for new organisms, apoptose is the eraser. It is a cellular self -destruct signal. That happens all the time in development when you need to erase the webbing in between fingertips that you form five disconnected digits in the finger, right? It's part of how we get rid of the premature tail that we develop in development, right. The balance between cell division and apoptosis is an extremely important part of How we form our tissues correctly in a developing embryo. And that's what I mean by in part that cancer is when things go like development in adult tissues. Because when you're an embryo, when you'RE an extremely young kid, you have a lot of growth you have to do. So you need a bunch of stem cells that are constantly dividing to grow those new organs, grow your body larger, right? It's only when youRE an adult and youRE done making new organs and you'RE done growing that you don'T need that rapid cell division constantly happening and it's going to throw things off. So that inability to recognize recognize apoptosis, basically goes, the cells know that something is wrong with their DNA, but there's nothing they can do about it because they've lost that self -destruct signal.

0:17:45 Eric: Another thing that happens is because when you make a tumor, normally your body and organs are connected through your vasculature, right? Through your blood vessels. But if I make a tumor, by definition, it's a new thing that isn't attached to our blood vessels yet, right. It's kind of disconnected from the cellular highway. And so an important step in development of cancer towards a really debilitating disease is it starts doing what we call angiogenesis. And angiogensis is basically when the tumor starts recruiting the types of cells and the structures needed to build blood vessels and vasculature that will eventually be part of its escape route into other parts of the cell, right? This is a big step in metastasis is developing vasculiture. But the problem is, is that vasculature doesn't develop until later in the tumor. And another hallmark of cancer is a shift in metabolism. Now, we talked a lot about this in the Hail Mary episode, but cells use oxygen in eukaryotes to do metabolism. We break down sugar to form ATP with a huge assist from oxygen as a metabolite, aerobic respiration. But cancer cells often switch to something called Warburg metabolism. Metabolism. And Warburg metabolism is when you don't use aerobic respiration, you use anaerobic respiration. Now that has benefits and weaknesses. The benefits for the cancer cell is that it happens much more quickly and much more easily. So you're basically the like really hyperactive hippo and hungry, hungry hippos gobbling up the available glucose, even if you're using it inefficiently, right? Because you're requiring a more steady stream of it than the cells that are using aerobic respiration. So you're channeling resources towards that. You're also in already non -functioning tissues, right? Which is another reason why cancer is both the thing that drives a lot of sickness and poor outcomes, but it's also a trailer of kind of what you've already done to your body throughout life. This is a big reason why smoking and cancer are so highly associated with each other, right, because smoking introduces that hypoxia. And so now you're you're actually favoring cancer cells over your normal healthy cells.

0:20:01 Eric: And so that switch to Warburg metabolism starts helping to grow the tumor out until it's now ready to then make blood vessels that it's going to use as its escape hatch. But by that point, it's already too late. And your cancer cell is already a mature tumor. Another thing that cancer is a hallmark by, is what we call invasion and metastasis. Now, this is the one that I'm more of an expert in than any other aspect of cancer, because this is where my protein grainy head like three comes into play.

0:20:31 Thomas: You go.

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0:20:46 Eric: Grainy head, like three in normal development is what we call an epithelial programmer.

0:20:51 Eric: Have you ever noticed that like back in old times, people would use things like sheep bladder or stomachs as like water skins and kind of airtight containers, right? Your cells that are epithelia, the ones that form like lining of organs, your skin, the lining of your stomach, all of those type of structures, are really, really closely stapled together with these proteins that we call junctional proteins. Your cadherins, your zoocludins, right? These are things that help really keep them together like a game of Red Rover or a rugby scrum. They're really good at forming those attachments, but that's good because it means that it's harder for cancer to spread when they're forming nice organized tissues that are stuck together. However, as you pick up more and more mutations, because you're dividing cells without that error check, without that apoptosis to get rid of mutations, you start developing mutations that attack that epithelial programming. And you do what's called EMT, epithelia to mesenchymal transitions.

0:21:51 Thomas: At what point are you just making this up? I don' t know. There's so many weird words.

0:21:55 Eric: One of my grad school friends who will talk about his project in a little bit, shout out to Eric. This is another fun story. Both of my closest guy friends in graduate school were also named Eric. So it was a very confusing friend group. What he would say is there is no such thing as EMT. There's just different ways to lose your epithelial status, right? Different ways to loose those junctional proteins, different ways to lose that connectedness. And that's similar to what we're talking about with cancer. There's no one thing that's cancer in the same way there's no one thing. That's EMT. There're different phenotypes, different properties that have similar characteristics.

0:22:07 Thomas: Sorry, what's the EMT again?

0:22:32 Eric: EMT is basically, I have skin cells that are closely connected, right? They're forming those junctional proteins that staple them together. They then lose those proteins that staple together and they start start behaving more like blood cells than

0:22:36 Thomas: Those ones, okay. Yeah, right. Why do they lose that?

0:22:47 Eric: Your epithelial cell because of mutations, right? They lose either mutations in the transcription factors like what I studied, where they're no longer turning on those epithelia characteristics or directly in those cadherin proteins, right, So they're not able to form those contacts. And that leads to a whole suite of rearrangements, both in the individual cell, where it's going to change the way its ropes and kind of cables, its microtubules and actin work to start promoting it to move around. And it doesn't have anything holding it together. And that's really your first step in metastasis.

0:22:51 Thomas: Okay, gotcha. Okay, so that's a kind of cancer, or it's happening because of a cancer or, okay, gotcha.

0:23:26 Eric: It's happening because of cancer to pretty much that is late stage cancer, right? When we start talking about cancer getting deadly and metastatic, we're talking about them losing that epithelial contacts and starting to travel throughout the body. Andthat's when you start getting cancer in multiple places. That's when it starts getting really problematic because you're not talking about one site where you can do surgery to remove the cancerous cells, right? You can't target one area with radiation anymore. Now it's a multi -stage problem and those cells are constantly traveling. So even if you remove cancer in one area, it might show up again in another area.

0:24:01 Thomas: Oh, how are cells constantly traveling? I never thought about that. How much does your average cell travel through the body?

0:24:06 Eric: Normally they don't. That's a really good question, right. Most of your cells, except for blood cells, macrophages, your hematopoietic system, most of your cell cells are what we call epithelial, right, they're forming that cell lining, they're staying in one place. They're also embedded in what we call the extracellular matrix. The extracellular matrix is like this mesh of protein and sugars and other molecules that kind of connect all the cells together in the same way like if you need to make like a, your kids have probably done this, it's like when you put a bunch of glue on a paper plate and put beads down and everything's being stuck together through that mesh of glue. Will. What cancer cells start doing, and this is what that friend Eric studied for his PhD thesis, is they start developing what are called invadipodia. Invadipodia are these small little finger -like projections in the cell membrane caused by a RAS -associated protein, and put a pin in RAS, because we will be talking a lot about RAS at the end of this. But it's a class of proteins that direct the rope inside your cell, what we call actin, that gives the cell shape, structure, and directs movement. And it makes like a little column, a little pillar, a little finger at the tip of the cell membrane. And it uses that to burrow into that extracellular matrix, that netting, degrade it, and allow the cell to escape. And they now have an escape hatch because they've done angiogenesis to develop the blood vessels. So they kind of make a hole in that epithelial tissue, escape into the blood vessel, and start spreading throughout the body. And this is when cancer gets really problematic, regardless of your subtype.

0:25:45 Thomas: That's crazy.

0:25:46 Eric: This is also why leukemia, before we dedicated lots and lots of money to finding good and responsive cures to that cancer subtype specifically, was so deadly back in the day. Because leukemia is your blood cells. They don't need to undergo that process of epithelial to mesenchymal transition, because they're already free -floating and traveling throughout the body. As white blood cells, they're already in those cellular highways, not connected to other cells. And so that's kind of the danger of like acute myeloid leukemia is you already have these cells that are primed for metastasis, whereas your epithelial cells typically require a progression into that metastatic state. Basically, the key is once they lose their property to be a skin cell, they're no longer able as well to function like a skin cell and hold barriers with other skin cells. But as you lose them in that barrier, they have to go somewhere. So they travel throughout the body, and then form tumors at other sites that then restart that process of building a tumor in that new organ, breaking down the extracellular matrix, forming blood vessels to allow for escape of that tumor into other parts to the

0:26:53 Eric: Body this is why the further you get into metastatic properties the more systemic your cancer gets the more systematic the phenotype looks right it goes from being like oh I'm a little tired here and there to I have just extreme fatigue towards the end of cancer development

0:27:10 Thomas: So is that one thing though, or is there a chance, is this like something that your cells are doing all the time and there's like a certain chance of some cells doing this when they're reproducing?

0:27:22 Eric: Great question it's something your cells do all the time in development when you have to make the organs and cells have to go from a pool of stem cells to wherever they're going to differentiate and become their adult tissue. And this is another theme of cancer is when adult tissues do developmental biology. Because once you're in your spot at the skin, that's when you enter senescence, become a good skin cell, stop dividing, but also stop moving around. You've now found your home.

0:27:48 Thomas: Yeah. I guess the thing I'm trying to figure out is like when someone has cancer, is it something that causes more of this or is it like enough of this has randomly happened to produce these effects or something? You know what I mean? I don't, I guess I don'T understand. Hmm.

0:28:04 Eric: It's a little of both because the key is that cancer cells, unlike your senescent cells, are constantly dividing. So there's more opportunities to develop the mutations that will randomly cause that epithelial to mesenchymal transition, whereas your normal cells aren't getting that opportunity, and they have those error check programs that would stop them before they start misbehaving too badly. Cancer cells don't have those breaks and checks, so they keep rolling the dice until they develop that epithelial-to-mesenchymal transition. This is also why certain cancer subtypes are much harder to treat than others. Ones that pick up mutations that more readily prime them for that epathelial mesenchymal with a transition are going to be way more aggressive in their metastasis, in their spread, in their progression, whereas ones that are more organized have mutations that don't lend itself to that epithelial mesenchymal transitions will stay in place a lot better. For instance, this dog has hip dysplasia. My old dog, who is kind of my soul dog because he was my pandemic dog, was named Chase. And he had osteosarcoma, which is bone cancer, right at his brain. But the thing that was both good and bad about that is the fact that it was at his brain means that we couldn't do surgery.

0:29:14 Eric: But he had a very particular subtype of that bone cancer, where it formed a very organized and structured tumor. And this meant that it was very slow to develop that epithelial to mesenchymal transition, which meant that we were able to treat the tumor for a period of about a year and a half before it grew enough to eventually go into his brain. But it wasn't really spreading to other parts of the body. So I was able to get a lot more time with him because it wasn't doing that by nature of that particular type of mutation. But if he had another subtype of that exact same cancer, osteosarcoma, it would have been a different mutation that caused different rates of epithelial to mesenchymal transitions that would cause spread to the rest of the body much more quickly.

0:29:56 Thomas: I think the part I'm not quite getting is now what is cancer? What does it mean to have cancer then? Like, is it when you have cancer, do you have, I've always thought it was just like you had these tumors or you had these growths or what are these cells that are growing out of control? Or is it that you have whatever it is that makes that happen? Because if it's not just like a random thing happening all the time, is there something that makes it happen in people that have cancer? Like almost like getting a disease where that makes it happen more often or something. I don't get it.

0:30:30 Eric: Yeah, that's a really good question. And it has to do with where we we were going to go next. And that there's two kind of major hypotheses for how cancer develops, right? Because you're absolutely right. We're more talking about the cause of the thing that we're seeing, which is the cancer itself, right? The cancer itself is the tumor, the misshapen cells, the ones that are ignoring the cell cycle, but they're caused by those genetic mutations. And so that led to one of two ideas. The first one is what we call the two -hit hypothesis. Hypothesis. The two-hit hypothesis is basically that either very early on in childhood when your cells are dividing a ton or from your parents you pick up one copy of the gene that is going to eventually be the downfall of these cells that causes cell cycle instability right either a mutation in those cyclins and kinases that tell the cell to stop or go forward or in the dna proof reading and the signals that tell cells to self -destruct when they know they're wrong that at apoptosis, right? For instance, have you ever heard of P53?

0:31:34 Thomas: I wouldn't know if I had.

0:31:36 Eric: P53 is a very, very famous cancer gene. It's in about 50 % of all cancer cases mutated, right, and what it does is it's basically the self-destruct button of the cell. It goes, oh, this DNA is damaged. Hit self-destruct. Now, P53's a little weird because it's what we call dominant negative, but many genes, right—you have one copy from your mom, one copy from your dad. So if you have one copy that doesn't work and one copy that works, oftentimes that one functional copy can paper over the one dysfunctional copy you inherited from parents, right? Let's say you got the BRCA mutation that primes you for breast cancer, right, until you get a second mutation that makes the other chromosome messed up or further stresses the pathway that BRCA is related to, you're going to be okay but then once you pick up a second mutation now it's not just that your genome is wrong and it's that the cells are truly behaving like that and that's when you start to develop the tumors the breakdown of the extracellular matrix the epithelial to mesenchymal transitions but all of that is primed from that initial mutation but you're right that we call it cancer once the physical aspects start showing up and

0:32:52 Eric: That usually happens later in life because you pick up additional mutations that further stress that cell.

0:32:57 Thomas: So that would be like having the predisposition, essentially.

0:33:01 Eric: Exactly. But until you fully knock out the ability of the cell to stop cell division, right? You fully knock out the inability for the cell of proofread the DNA. You fully knocked out the ability for the cells to self -destruct. You won't have true cancer yet because the cells are still behaving like normal. Another theory that I really like, not just because this was suggested by one of my committee members back in graduate graduate school, is what we call adaptive oncology. And what that is basically saying is most of your cell divisions don't happen later in life. So most of the mutations that you're going to pick up from mistakes in DNA replication are actually going to happen in development or as a very young kid as you're growing tissues, as you'RE doing this organ genesis.

0:33:45 Eric: And so cancer cells, as we just talked about, behave very, very different from your normal cells, They have a different metabolism. They have more mutations. So they're technically less fit than your normal cells, which evolved to be fit. But as you do things like smoking, get chronic wounds that cause inflammation in your joints or your tissues, that's going to alter the way that the microenvironment those cells sit in presents itself. And if you constantly have hypoxia, a lack of oxygen in that tissue, the cancer cells that don't need oxygen to do metabolism are now going to go from being under -competed because oxygen is more efficient to get energy to out -computing the normal cells because when there's a dearth of oxygen, the ones that can do growth without it now have the advantage. Does that kind of make sense?

0:34:36 Thomas: I think so. So what causes your cells to not get oxygen? That's the, were you saying smoking does that?

0:34:40 Eric: Yeah, smoking, inflammation, right? So if you have like chronic wounds in an area that can lead to hypoxia or inflammation in that area, lots of different environmental effects can cause the microenvironment to be shifted and change that selective landscape from favoring healthy cells to now favoring your defective cancer cells. And so you can kind of think of it as one of them, the cancer was there all along and it was waiting for its opportunity to shine. And the other one is it's ready to become cancerous. It's just waiting for that final mutation, that final step to transform it into a truly cancerous cell.

0:35:19 Thomas: What do you mean when you say it? What's the it?

0:35:22 Eric: It is a mutation that will finally cause the cell to become cancerous, right? So before it's damaged, but fine. And then like, for instance, since it's 105 degrees out in Philly, sunlight is a big cause of skin cancer because ultraviolet rays are radiation, right.

0:35:24 Thomas: Okay, gotcha. Okay, hmmm,

0:35:40 Eric: And what they do is they cause thymine, the T in your A, T, C, and G of your DNA to become cross-linked together when you have two adjacent thymines. So now you don't have a nice spiral double helix. You have these two thymines that are stuck together that causes like a kink or a bend in the double helix that throws off the protein that replicates your DNA because the structure of that DNA is now changed. And when it replicats, it doesn't really know what to do with that kink. And so it throws in the wrong base pair because the infrastructure is not there. Tell it the right thing anymore. And then you pick up that mutation and that mutation leads to skin cancer. So that clearly happens, right? We do pick up mutations later in life that prime us for cancer or that develop cancer. But it's also true that most of our cell divisions happen very young in life. So it's likely that most the cells that will eventually form tumors were already quote unquote cancerous. They're just being out -competed by healthy cells until the micro

0:35:40 Thomas: Hmmmm.

0:36:39 Eric: Microenvironment shifts into one that's more helpful for them.

0:36:41 Thomas: Are they out-competed or does your body fight them?

0:36:44 Eric: Both. So I forgot to mention this. A big hallmark of mature cancer is they lose the ability to be detected by the immune system and be cleared by your immune system. We have these type of molecules on the outside of our cell membrane called MHC molecules. And these are the secret handshake to get into the club, the RFID reader you scan at the door of your office building, right? They're the way to know you are a part of the body. Cancer cells lose these, but don't present new ones that are strange. And in a way, like the same way that type O blood doesn't trigger an immune response, they become like type O blood in that they avoid detection from the immune system.

0:36:45 Thomas: Both, okay. Ah, Geez. One thing that I keep thinking when you're talking about this and you're talking about how the cancer travels and all that is it sounds like so adaptive or whatever, but like that doesn't make sense because it's not like cancer is like its own organism that's trying to thrive in a way. Right. Or or what?

0:37:43 Eric: No, you're actually right. Because remember, trying to thrive is the human lens on this, right?

0:37:48 Thomas: Like, yeah, right.

0:37:49 Eric: All survival in biology is a passive process where you're being filtered through selective pressures. But cancer is constantly trying to reproduce. It's only when selection selects for it that it will start to grow into a tumor. Exactly. And that's when the immune system starts to get overwhelmed. It also loses some of those properties to be detected by the immune system. And now you have this tumor that's growing in relative peace.

0:38:02 Thomas: Outproduce. Yeah. Right, yeah.

0:38:15 Eric: And this gets compounded by the fact that you've now integrated into the vascular system through angiogenesis. So you can now avoid detection in the blood vessels because you are producing radically different proteins on your cell membrane that changes the way your immune system interacts with those cells.

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0:38:48 Eric: So that's kind of how cancer develops. And I should mention, cancer is not just a human thing, right?

0:38:54 Thomas: Right?

0:38:54 Eric: This This is pretty conserved throughout all animals because all animals have complex tissues that require cell division to grow and develop them.

0:39:03 Thomas: So it's not as though well, I'm sure there's, you know, like the sun, the smoking, there's behaviors that lead to it. It's not as though the wooey idea that like the things we do, like created cancer, whole cloth, probably not true. Right. It'S not like if we went back to caveman times, it's not like that would solve all of cancer. I'm guessing.

0:39:20 Eric: There is evidence of dinosaurs with cancer.

0:39:23 Thomas: Jeez. What were they smoking?

0:39:25 Eric: This is probably ingrained from, there's a huge split in animal evolution. We have our radially symmetric animals, our starfish, our jellyfish, right? They're symmetrical in a circle. And then we have our bilateral symmetrical animals. And this is pretty much everything else, right? If you notice your left and your right side are mirror images of each other.

0:39:46 Thomas: Holy shit. Never. No, I'm just kidding.

0:39:48 Eric: Yeah. Right. And this bilateral symmetry leads to complex tissue and cellular organizations that prime itself for disruption by cancer, especially because to repair these tissues, you need to do a lot of mitosis. And so one reason why cancer develops later is an evolutionary story. We do a great job of maintaining our cells and the microenvironment our cells live in for the beginning parts of life, This is part of the reason why there's much less scarring when babies heal a wound than when an old person heals a wound. And a big reason for this is because evolutionarily speaking, and again, this is anthropomorphizing it, right? This is all passive results of statistics. Statistics but by the time you're 40 if you were going to have kids you've already had kids there's no real pressure anymore to make sure that you are maintaining your health and safety because you've already done your job in evolution terms of passing your genes on to the next generation so your genes aren't going to make a choice to waste time and energy maintaining the body and microenvironment later on in life whereas the younger you are the less likely it is that you have had kids yet. So there's a vested interest in maintaining your peak fitness. So one of the reasons why cancer develops later in life is because there's less selection in your later years than there is in your earlier years. With that said, there are some animals that can avoid cancer entirely. And a famous one is the elephant.

0:41:14 Thomas: Really?

0:41:15 Eric: Yeah.

0:41:15 Thomas: That is not what I would have guessed. I would have guess they've got, they got so much surface area, you know, to have the cancer. It's so much mass.

0:41:22 Eric: Yeah, what's really cool is you tripped up on a paradox that is found in biology called either Peto or Peto's paradox. I've only read We're going to go with Peto for obvious reasons.

0:41:32 Thomas: Either way they were on the island.

0:41:34 Eric: Right. But pedo's paradox is why don't we see super increased rates of cancer in these large vertebrate organisms that are going to need to do a lot more cell division?

0:41:44 Thomas: And also what should the age of consent be really is, sorry.

0:41:48 Eric: Well, evolutionarily, it's whenever you've had kids.

0:41:51 Thomas: That's why it's pedo's paradox.

0:41:54 Eric: Right? Right. But elephants are able to avoid this because they have 20 copies of that p53 protein. They're really good at avoiding those anti-apoptotic events. They will always be able to hit the self-destruct signal when cells start to get abnormal and look mutated. So they're really good at that. Whereas whales, another really large and long-lived organism, does the opposite.

0:42:20 Eric: Instead of having 20 copies of p53, they have the best copy of p53, you could fashion right, it has been selected down to a work of art that's extremely resistant to common mutations that will alter its structure. And it's really precise in editing DNA.

0:42:36 Thomas: So they also don't get as much cancer you're saying?

0:42:39 Eric: Exactly.

0:42:40 Thomas: Do they get zero cancer or just not as much as we'd get it?

0:42:44 Eric: A good rule of thumb in biology is nothing is zero and nothing is 100. Just as a general rule of thumb, pretty much anytime I say something like they don't get it, just assume that that's an over exaggeration. And we're really saying in comparison to other beings. Another fun one, though, is naked mole rats. And the reason why I want to bring up naked mole rats is they don't go for increased fidelity of DNA replication or increased P53. They're all about regulating the micro environment. They have these specialized sugar structures in things like their extracellular matrix that prevent the clumping that's associated with tumor formation, right? They help disperse them and make sure that they they don't form these pockets where oxygen is no longer able to travel because there's no blood vessels in that tumor.

0:43:28 Thomas: I'm hearing is how easily we could sell out and do pseudo woo science stuff. Like all you gotta do, you gotta find one of these things. Don't listen to anybody who's bad. You just gotta find one of These Animals. Hey, this animal never gets cancer. You know why? Because it regulates its environment like that. So therefore, get in my pod that I'm selling for $10 ,000. It regulates your environment so that, you know what I mean?

0:43:56 Thomas: Like there's so many opportunities for bullshit in this because of how complicated it is.

0:43:56 Eric: And that's why there's also that opportunity to go, oh, well, there's definitely a cure for cancer. They're just hiding it, right? Because we're not even up to the third or fourth layer of the complexity of cancer. But you're absolutely right that scientists are actually using these as fruitful avenues of research. It's just really hard to actualize these into therapies, right? Because tissues are very, very complicated once you start building in all of the parts of the body. There's a very famous, I forget what the comic strip is called, it's like XKCD or something.

0:44:30 Thomas: Oh, yeah. XKCD.

0:44:32 Eric: Yeah, there's a very famous comic strip from that, where it's talking about the pitfalls of cancer research and cell lines, where he goes, and shooting it with a gun proves to kill cancer cells 100 % of the time, right.

0:44:42 Thomas: Yeah. Yeah, it's like the thing where they say, hey, they could kill it in a Petri dish. It kills it in Petri dishes. And they're like, yeah, also shooting it with a gun would kill it in a Petri dish.

0:44:53 Eric: Exactly. But one, one, you're removing the rest of the body context from that plate of cells. Now, here's where it gets interesting talking about cell culture, though. It's true that we do a lot of cancer research in cell culture. We also do a ton of research in cancer research. We do a whole lot of non-cancer research in cell culture, and that can lead to a lot of problems. Because if you work in a lab, you kind of want to work with cancer cells as one of your models for cell culture because you don't have to keep isolating them over and over again. Them, they're going to keep dividing and dividing and dividing over and over again. And so a lot of the famous cell lines that we use in labs are actually what we call immortalized or cancer cell lines. You've probably heard of the book, The Immortal Life of Henrietta Lacks.

0:45:38 Eric: She's famous for having a cervical cancer cell line that became one of the backbones of biological research called HeLa cells, Henrietta Lacks cells. And these are cancer cells that we use in a bunch of other contexts. And I would argue this is part of the reason we have a replication crisis in biology for two major reasons. One is scientists often are not great when they publish their papers of tracking what passage number those cells are in, how many divisions those cells underwent before you did the experiment. But we just talked about how cancer cells pick up a ton of mutations as they divide because they have unrestricted cell growth. So depending on how how many times you've passaged your cells to allow them to divide, you may have picked up mutations that you don't know about that's fundamentally altering the results of your experiment. But not only that, if you're doing non -cancer research with these cell lines, you have a giant caveat that these cells behave different in a metabolic sense, behave different In response to growth factors and apoptosis signals, right? So I remember there was one lab meeting, where I was dealing with a collaborator in my lab, who was talking about the research she was doing on an experiment that involved these HeLa cells. And she was talking about how apoptosis is altered once you delete a certain gene. And I told her basically straight up, I'm not sure you can use these cells for this experiment because you're dealing with cells that already have altered apoptoses.

0:47:01 Eric: But unless you're actively thinking about that, you're going to publish papers that are correct in the micro sense, but lose that bigger picture of the exact context you're doing that research in. The story we have so far is that cancer is basically unrestricted cell growth that causes mutations to occur that will affect things like the way that they behave as epithelial cells, causing them to travel throughout the body, the way they deal with oxygen in their metabolism, causing then to out -compete in damaged tissues, and the way that they respond to growth and self -destruct signals, and they way they interact with the immune system. And that's going to start setting the stage for how we can go about treating cancer, both in specific cases and broad cases, and why it's really hard to come up with one cure for cancer.

0:47:47 Thomas: Well, yeah cuz it sounds like everything we've talked about sounds like a condition you have, like, even if you could get a tumor out or something. It sounds like, well, this is what your cells do now. So maybe I'm wrong.

0:47:58 Eric: Right. That largely depends on how far along the metastatic pathway they got. If my dog's really organized tumor was on his leg instead of his brain, we would have been able to cut off that leg and he would have been cancer free because none of the cancer cells had spread yet. But once they start metastasizing,

0:48:18 Thomas: I see. But now this is where I'm struggling. So I'm still really struggling with if that's true. So why isn't it that your dog or whoever would just develop another tumor somewhere because of whatever preconditions made it so that they developed it? Is it because it can be, like you said, places where you've had trauma to cells over time? So it's like if there's one spot that's more prone to cancer because of, you know, whatever you're talking about, lots of wounds, smoking, sun, whatever. Is it because of that? Because I still don't get, it still feels like having cancer is still the preconditions for cancer.

0:48:52 Eric: It's both. Yes. One, there are certain hotspots that are primed for cancer, either because of their placement in the cellular highway of your blood vessels, right? They're easy for cells to travel to, or because they're already got a damaged microenvironment that helps that selective landscape. But remember that cancer helps breed itself and push those conditions along. Because if I have a giant tumor that's crowding out the blood vessels in that tissue, I'm going to introduce even more hypoxia into that tissue. So you start to slowly lean on that organ and push that microenvironment to a pro -cancerous one. And not only that, because I'm not using oxygen for my metabolism, what available sugar there is is much easier for me to gobble up even if I'm Not using it as well. And so you can start with not a little bit of cancer, but a cell that's primed to cancer. And then over time, it will will slowly start shifting that balance both in its own state and in the micro environment to make it easier for that cancer to take hold. But you're right that that's part of that disease progression, right? You'll have cells that do that EMT before you get full tumorigenesis in a distal body part, right? Before you get another tumor developing somewhere else. And it's from those repeated attacks, right? From the fact that your immune system is no longer targeting it and they're free to kind of start building up slowly over time that you then get those tumors to spread in other areas, if that makes sense.

0:50:15 Thomas: I guess so.

0:50:16 Eric: In part two, we can talk about the broad ways that we treat cancer and things like that.

0:50:21 Thomas: Yeah, that's right. You got to get a part two to get the cure for cancer, guys. It's at patreon.com/seriouspod. We got the cure.

0:50:27 Eric: I'm paid for by Glasgow Smith. You can, you know, no. Where we're at right now is that the reason why cancer is so hard to treat is because all of those mutations, that disruption of the cell cycle is going to make it so that every cancer is super, super different from every other cancer, especially once they start building the tumor. Because my mutations are going to cause slightly different alterations in the pathways that control cell division, apoptosis, immune detection, than other cancer subtypes. And not only that, because mutation is now baked into this, even within my own tumor, I'm now going to have different types of cancerous cells just within my own cancer cell tumor. Because one cell dividing that has a broken DNA repair mechanism won't necessarily get the same mutations as another cell in that tumor that's dividing with broken safety checks.

0:51:24 Eric: They're both free to get mutated in different ways. And so tumors are often what we call heterogeneic. They have many different cells with many different mutations that complicate treatment options because now you're not just fixing one thing, you're fixing many things within the same tumor.

0:51:24 Thomas: Man, that sounds hard. Yeah.

0:51:43 Eric: It's very, very hard. And so we can start with this as a teaser for like the next gen. This is why different cancers have many, many different outcomes, right? Pancreatic cancer, colon cancer, leukemia, and lung cancer all have different fatality rates, different times to metastasis, right. And part of this is because different different mutations prime yourself for different types of cancer in different tissues in different contexts. And so like aggressive small cell carcinomas in the lung are very, very aggressive and hard to treat and deadly because your lungs are already highly connected to those cellular superhighways, right?

0:52:01 Thomas: Oh, right. Yeah.

0:52:24 Eric: Your lungs by definition are trying to spread things to your entire body already. And So often by the time you've detected the cancer in the lungs, it's already hitched a to ride to other spots.

0:52:35 Thomas: Man.

0:52:36 Eric: Pancreatic cancer is more the opposite, where the reason why it's so fatal is because you're often not detecting it until it's already become the more aggressive form, and it's very hard to surgically treat in its less aggressive form because of its location.

0:52:52 Thomas: Right. So it's possible like a lot of people just have it and it's not affecting them until it gets to that point.

0:52:58 Eric: Exactly. And by then, you're already in a different stage of cancer progression where it's already spread or it's already ready forming such deleterious effects. Whereas leukemia used to be a huge problem and some subtypes still are but because we've gotten much better at detecting it and removing it from the bloodstream with our immune cells it's become more treatable than certain other types although even that is variable within your subtype of leukemia every cancer every human is their own unicorn and that's going to bring us to part two when we talk about the next generation of cancer treatments, where you're not thinking of one cure for all cancer, you're thinking of certain processes that you can use to adapt to different types of cancer, right? You're personalizing the cancer treatment.

0:53:46 Thomas: Interesting. All right. We're going to make it personal.

0:53:51 Eric: So next episode, we can cure cancer.

0:53:53 Thomas: Yeah, let's do it. All Right. But you got to listen to the show to get the cure. Well, this is really interesting. It's always tough to follow these, but I do think by By the end, I got a good picture of at least several of the different kinds of cancer going on. Really, really interesting. I learned a lot. I'm excited for part two.

0:54:11 Eric: If you want like a three sentence summary of where we're at, the difference between cancer and normal development, both involve rapid amounts and massive amounts of cell division to form new things. But in development, you're supposed to do it and you have the safety checks and structures in place where it's a nice organized activity. Whereas in cancer, you haven't baby proofed the house anymore and you Have a toddler running amok right in development. You're expecting this stuff to happen. So you have all the tools in place and the environment is fit for those rapid amounts of division and cancer. You are no longer fit for Those things. You Are not expecting it. And so even though it's stuff that you do all the time as a baby in an embryo, it's now no longer the right context, and it can cause really hard effects on the body.

0:54:36 Thomas: Oh, yeah, you got rid of all your baby proofing. That's a good one. That's an analogy.

0:55:00 Thomas: Wow. All right. Anything else you need to leave the audience with?

0:55:03 Eric: Book end to the last episode. This is something where I will fully admit I'm really good at the epithelial mesenchymal transitions and the molecular underpinnings, but the clinical stuff, especially for next episode, is not an area of strength. So please, if you have any questions or comments, please hit me up at elj2117 at gmail .com, and I will happily address any corrections or concerns in the next episode I record.

0:55:26 Thomas: All right, wow. Giving out your personal email. Nice. You could also email me, maybe. Yeah, we'll forward it, I'm sure.

0:55:33 Eric: Either one works.

0:55:35 Thomas: Awesome. All right? Well until next time thanks so much geez

0:55:37 Eric: Always a pleasure. There is evidence of dinosaurs with cancer.

0:56:00 Thomas: What were they smoking either way they were on the island