The Evolutionary Theory of Cancer (podcast)

"Cancer cannot do anything new", Vaccine for cancer, Atavistic theory

Aastha Jain Simes is the creator of Live Longer World, a podcast and newsletter where she interviews scientists researching the frontiers of longevity science and biology.

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The following is a fascinating interview on cancer biology with Dr. Charley Lineweaver, whose research ranges from astrobiology to evolutionary biology and cancer (transcript below). His work on cancer was done in conjunction with Dr. Paul Davies, renowned scientist and author of several popular science books. Topics include:

• the evolutionary and atavistic theory of cancer

• the incorrectness of the somatic mutation theory of cancer

• a novel take on attacking the weakness of cancer

• how embryogenesis could be viewed as cells reverting to old memory

• the origins of multicellularity

• “Cancer cannot do anything new”

The atavistic theory of cancer states that cancer cells revert to an old memory they have from billions of years, but forget the new memory. The old memory pertains to constant cell proliferation, which happened as single-celled creatures, and in fact in embryogenesis as well. The new memory pertains to regulating cell proliferation and cells knowing when to stop cellular division. In cancer, it seems like cells forget this new memory and revert to the old memory.

This theory has many deeper explanations and predictions which we dive into in the conversation. Enjoy!

Papers referenced / Relevant Papers:

• Cancer progression as a sequence of atavistic reversions

• Targeting cancer’s weaknesses, not its strengths

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Timestamps:

0:00 Background in astrobiology

1:53 Evolutionary theory of cancer

6:22 Atavistic model: Cancer cells go back to “original state”

9:50 Atavistic theory vs. Cancer

14:44 Somatic Mutation Theory of Cancer is Wrong

22:36 Disagreement with Michael Levin’s work

24:17 Attack the weakness of cancer

27:45 Vaccine for cancer

38:08 Wound healing and cancer

41:23 Why new genes are more susceptible to damage

45:26 Origins of multicellularity

48:49 Predictions of Atavistic model

53:45 Cancer cells spread

56:52 Cell proliferation, Cancer, Hayflick limit

58:54 Doctors are not trained in evolution

Transcript

Aastha Simes: My name is Aastha Simes and welcome to Live Longer World. Hi Charley Lineweaver and welcome to the Live Longer World podcast.

Charley Lineweaver: Thank you Aastha.

Aastha Simes: So I actually stumbled upon your research while listening to another podcast and I thought your theory on cancer was really fascinating so I reached out to you. But before we get into the weeds of cancer, you have a background in more astrobiology and cosmology. So how did you get interested in looking at cancer?

Charley Lineweaver: Okay, nice question. Well, I did my PhD at Berkeley and we looked at the microwave background radiation. So I'm a PhD cosmologist. And when I was doing my first postdoc, or actually the second postdoc, planets were discovered around other stars. So the first exoplanet, I did my PhD in 1994. And in 1995, a planet was found around another star. And then the whole world of exoplanets exploded. And so I, we started getting involved in astrobiology, which is essentially, well, actually there was a show called, uh, what is it called? I want to believe the truth is out there. What show is that? The X-Files. And the X-Files says the truth is out there. And all these students were really watching. It was very popular. And I said, well, wait a minute, I'm an astronomer. We know about the truths that are out there. Those Hollywood producers don't know anything about what they're writing about. They're just inventing stuff. We know. We're the astronomers. We know what truths are out there, or at least the closest that anyone else knows.

So we decided to start a course called Are We Alone? And I did that with some colleagues at the University of New South Wales in Sydney. And in the process of studying, trying to understand life on Earth, basically, you have to study four billion years of the evolution of life, all four billion years, because that's how long life has been on this planet. You know, the Earth is four and a half billion years old, and life probably got started after about a half a billion years. And so four billion years is a long time. And about two billion years ago is when multicellularity evolved. That is big things like you and me. We have about 50 trillion cells, and things like us did not exist about two billion years ago. So for the first 2 billion years, there were colonies of single-celled organisms, but not really multicellular things like us.

Now, the reason why that's interesting is because cancer seems to be a malfunctioning of the genes that are responsible for differentiating cells into a nose, a chin, an ear, an eyeball, et cetera. So the evolution of multicellularity is something that's very important. This is a very important feature of life, the evolution of life, these long four billion years. Now, so here we were scientists studying astrobiology and four billion year history of life on Earth. And then we heard about cancer. And a lot of people say, oh, cancer is a disease of multicellularity. It's a disease of reproduction.

Then we said, well, wait a minute, this didn't even exist earlier. And then then cells had to learn how to stop reproducing. For example, you used to be a single cell, then you were two, then you were four, then you were eight, et cetera. It just keeps on going, going, going during what's called embryogenesis. But that reproduction, which is really fast, has to slow down and then it has to stop. And there was a scientist called Mr. Hayflick who figured out what's now called the Hayflick limit. And that is these cells go through a doubling of about 40 doublings and then they stop. If they didn't, you would just grow things like cancer all over the place.

So, cell proliferation had to be controlled by an evolving set of regulatory genes that say, okay, genes, okay, mitosis, stop. You've had enough, you've done your duty, you've turned into lips, you've turned into shoulders, and that's it. Now, cancer seems to be something going wrong with that control. Cancer is unregulated cell proliferation, so it's as if those mechanisms to stop just fall apart, and the cells revert to what they used to do early in embryogenesis, but significantly earlier in phylogenetic history. In other words, two billion years ago, there were no constraints, and cells just go, mitosis, mitosis, mitosis, reproduce, reproduce, without any care about becoming differentiated into a nose or a bone or et cetera.

So this is the story that we found out and learned about. And then we found out that talking to doctors, they have no idea about the evolution, the 4 billion years history that we had become experts in because we were so concerned about the 4 billion years history of life on Earth. Why were we interested in that? Because we wanted to figure out if you can understand the origin of life, you can figure out whether life originates on other planets. So by dint of wanting to know more about the origin of life on Earth in the four billion year history, we became experts in the evolution of multicellularity, which I think, and many people think, is integral to understanding what cancer is. In a way that doctors had no idea.

Doctors will give you a pill, their job is to try to cure you, to try to save your life. And for some reason that does not involve 2 billion years of, or 4 billion years of evolution and how cancer lost this ability or that ability, they are really not interested in that. They're saying, is there something we can do to save this person's life? And that somehow precludes knowledge of the origins of cancer in, I mean, the evolutionary origins of cancer. So that's why this idea of an atavistic model is something that doctors don't think about. And so we could add something to the debate by developing this model further.

Aastha Simes: So you said something there, which is that cancer cells go back to the original state that we came from, our ancestral state. What does that mean?

Charley Lineweaver: Okay that's what atavism means for example sometime now what is an atavism sometimes people are born with uh gill slits here they're proto gill slits right here because we 400 000 years ago were fish um our ancestors were and sometimes you have what are called supernumerary nipples I think the guy in Planet of the Apes Mark. Somebody, Mark, who's the star of Planet of the Apes, the new version? Anyway, he has supernumerary nipples. Some people, normally you have just two nipples right here, but there's what's called, there's a node here. Now other creatures, our ancestors used to have more than two nipples. So, but, let me go back. Our ancestors used to have tails.

So when you look at an embryo, a human embryo, at about three months or four months old, you will see a tail. But you then get signals, say, okay, we don't need a tail, turn it off. And so then you have apoptosis. That's just the cell death of something. So instead of having the tail develop, it just atrophies, and then you are born without a tail. Now, if you are born with the tail, something has gone wrong with the suppression of that tail, which is the suppression is normal. If you take away that suppression, then people are born with tails. Uh, we only have two nipples. If you take away the thing that used to be multiple nipples, you take away the suppression of multiple nipples and people are born with multiple nipples.

And so for example, Alexander, the great, I think Caesar had three toed horse horse. Now horses had five fingers and then they had three and then they had one. And if, and so phylogenetically, that was the evolution of a horse's one digit. But if something goes wrong with the suppression during embryogenesis of that getting away of the other digits, then the horse is born with three digits. So that's an example of an atavism. It's called a genetic throwback.

Now, what's interesting about these things is they are not only what we used to do. So for example, so supernumerary nipples. It's not only something that we used to do, it's also something that appears in embryogenesis early on. So, so, for example, let's talk about cell mitosis. You have to divide, divide, divide, divide. That's something that we used to do 2 billion years ago, but it's also been kept because that dividing, that mitotic is needed during embryogenesis because you need to turn one cell into 50 trillion. And so you need to divide, divide, divide, divide in an unregulated way, very, very early in embryogenesis. Then you have to differentiate and then you have to turn it off.

So the regulation is new. The unregulated proliferation happens early in embryogenesis, but it also happened early phylogenetically 2 billion years ago. So the atavistic model at the same time predicts things that were necessary early on in the life of an individual ontogeny is a fancy word for that. Or, and simultaneously, it's something that evolved very early.

Aastha Simes: So if your cells do, well, I guess if you get cancer and your cells are going back to this atavistic state, why is that necessarily, why is that killing our body? For example, someone who's born with multiple nipples, I'm guessing they don't have cancer, right? Maybe it could develop into cancer. Definitely. They're fine, right. So what's the difference between getting cancer versus just having some atavistic cells and not having cancer?

Charley Lineweaver: Okay, so the atavistic things we talked about are the gill slits, having more hair, having webbing between your toes, having supernumerary nipples. These things are morphological atavisms that are harmless because they do not include, they do not include unregulated cell proliferation. They just, hey, they said, hey, we're not gonna, we have genes that suppress the toes in the horses to make them like this, but you know what, the genes are, something's wrong with them, and so what comes out of this? But nothing bad happens except for the fact you have a three-toed horse or a little semi-nipple here along the breast line. So that's not bad at all. It doesn't do anything bad.

What's problematic is if the Hayflick limit, the regulation that turns off mitosis, if something goes wrong with that, then you revert to the earlier stage, which is unregulated cell proliferation, and that's turning, turning, turning, and then you get something just grows, grows, grows. And it's kind of like a wart that won't stop or a wound that won't heal. And that's problematic.

Aastha Simes: I see. So when you have this unregulated cell proliferation and then cancer cells keep growing, and that's when you realize, okay, these cancer cells are progressing into an atavistic state, which is going back to the original state that the cells were.

Charley Lineweaver: I wouldn't say there is no such thing as an original state. What they do is, one way to think about this is there's 20,000 genes. Each of those genes, some of them are really new. They evolved in the last 10 million years or 20 million years. Others are older, 100 million years. Others are really old, 500 million or even a billion or even 2 billion or 3 billion. So of the 20,000 genes we have, you can associate ages with them. And so in the atavistic model, it says that in cancer, what's going wrong are the genes and the regulation of the genes that have evolved most recently. And because of something wrong with this recent stuff, it reverts to something that is more protected and older. And, uh, so it's like an atavism with these nipples, you know, when something goes wrong with the, just getting rid of this nipples, what happens? The old stuff shows up just like our ancestors, I guess. I'm not sure how many, maybe 50 million years had multiple nipples, not just two, but four then like dogs. How many do dogs have? Maybe they have eight, four pairs.

And, uh, so during, during embryogenesis, you said, okay, I'm starting to make eight nipples and they say, oh, wait a minute, you're going to be a human being. You've got to suppress those other pairs and then you have to. And so the same thing happens with the, like webbing, you know, we used to be fish and we had that webbing between, and then it says, wait a minute, you're going to get rid of the webbing between your fingers. And so you then have five digits rather than fins over here. But those are harmless morphological ones that have nothing to do with cell proliferation. The problem is when you have atavisms that affect the stuff that regulates cell proliferation.

There's a whole, you know, if you look, if you study the cell cycle, which is essentially what happens when a cell reproduces, there are all kinds of phases that it goes through and there are checkpoints. And, you know, if there's, if, you know, the Hayflick limit that we mentioned has to say, well, you've differentiated, you turn off, you can't do anything. And what's interesting is if you get a cut on your hand, then the cells there have to start going back to proliferating, right? They have to fix that thing. And to do that, they have to say, wait a minute, there's something wrong here. I have to start my dividing again in order to make that scar tissue and heal up the thing. So this whole wound healing is a little like, okay, I've got to start going back to proliferating like I used to do when I was a baby, like a fetus. But then it has to be regulated as soon as it heals up then you have to stop and that's the regulation of it now if that reg something's wrong with that stopping if the policeman doesn't come out and say stop then you have just regulation you have just proliferation going on and on and on.

Aastha Simes: Why do you think cancer cells are becoming atavistic?

Charley Lineweaver: I wouldn't say they're becoming I would say that cancer cells are due to all kinds of damage to the more recently evolved mechanisms that essentially control cell proliferation. So let me, so that is what, ask the question again in a different way maybe?

Aastha Simes: From what I understand, I think, part of your theory is that, well, cancer cells, obviously, we all know, have this unregulated cell proliferation. But they're also reverting to this atavistic state.

Charley Lineweaver: Which is the same thing. An atavistic state was what it used to be. And what did cells used to do? Just proliferate. There was no constraint on them 2 billion years ago.

Aastha Simes: I see. Okay. I was imagining there is more than just a cell proliferation that's happening. Maybe certain other types of genes being turned on.

Charley Lineweaver: Oh, there is. There are many, many, many. There's some nice papers about the hallmarks of cancer. So it's not just unregulated cell proliferation. For example, there's something called the Warburg effect. And the Warburg effect, have you heard of this? It's when you have cancer cells are different from normal cells. Cancer cells, by the way, they're not viruses and they're not bacteria. They are your own cells, which are something is wrong with. And what we're trying to do is describe what is wrong with them. And the atavistic model is one way of describing that.

I should point out that our model is a minority model in the sense that to the extent that doctors think about this at all, they usually subscribe to the conventional model, which is sometimes called the somatic mutation theory. Now, somatic mutation theory is not a reversion to earlier cellular behavior. It is the following. You have a cell which is damaged, and then there's a lot of mutation, and you create all kinds of who knows what, and then you select. Evolution goes on during the couple of decades that these damaged cells are in your body, and then you select, and then it figures out how to do A and figures out how to do B. and figures out how to do C, and then you select again and again, and then these cells have the functionality to out-compete your own cells, and then they just go crazy. They're rogue cells. But it's the effect of normal, not normal, but Darwinian evolution, I call it interior Darwinism, during a few decades, are supposed to produce all of these marvelous abilities that cancer cells have that make them so dangerous. And I think it just doesn't make sense at all. But I should say that's the conventional model that you'll hear most people talk about. And I think our model is much, much better and it's testable in ways that the somatic mutation theory is not. But most people who are working on the cancer subscribe to what I think is not a very good model. And I've written a paper about that, a couple of papers, actually.

Aastha Simes: Okay. Can you talk about some of those papers? How would you compare those two models?

Charley Lineweaver: So there's a chapter I wrote with Paul Davies. Most of this work, by the way, is with Paul Davies and also with a Canadian oncologist named Mark Vincent and some other people, like Kim Bussey at Arizona and Blackmore at the where I am at Australian National University. In any case, this is the atavistic model we've developed. We've probably written about a dozen papers on this model. And so I wrote a paper about comparing the atavistic model to the somatic mutation theory model.

And the atavistic model makes all kinds of predictions. Why? Because if you're going to revert to something, you're going to have to revert to what the cell used to do. There's no other alternative. So what you're doing, and here's the interesting thing, those abilities are already in every cell of your body and they're used mostly during embryogenesis because that's when cells proliferate like crazy and they don't have full, your arteries and your blood system in the very beginning is not very well developed. So these cells have to deal with hypoxia, environments with low oxygen, and cancer cells are really good at doing that. And in the fetus, because you do not have well-articulated arteries, then the cells have to grow in a hypoxic environment. So cancer cells are like that.

And anyway, if you're restricting the functionality of cancer cells to be what cells used to do. That's a very narrow thing that can, and you can figure out what cells used to do by using phylogenetic trees. So for example, we have us here and chimps here, and you go back and say, oh, what genes were shared by us too, but not shared by gorillas, for example. And so you can give the, that's how we do phylostratigraphy to get gene ages. And the prediction of the atavistic model is that the new genes are the ones that something goes wrong with. And you then the whole body of the cells then rely on the older genes to do all their business, which they're unable to do the things that evolve more recently.

In the somatic mutation theory, you have a cell in your body and something goes wrong and then it proliferates. And when it's proliferating, it's produces all kinds of mutations. These mutations are then selected for and you say, oh, those are died those dies, but this one survives and then it reproduces and then then it proves a bunch of mutation than this one. And so in this way, it's kind of like taking normal Darwinian evolution and pretending that it could happen on a decade scale to produce all of the marvelous abilities that cancer cells know how to do. For example, you have to start over here, they have to get into the blood system, metastasize and spread everywhere, provide, you know, and attack things. They have to out-compete your own cells in your body.

Now, these are your own cells that something has happened to. The atavistic model is very precise about what has happened to them. The hallmarks of cancer are consistent with this atavistic reversion, but somatic mutation theory says, anything can happen, but by the way, these specific things happen. So it doesn't predict anything except selection is the driving force. And selection can be the driving force to produce all kinds of functionality if you have billions of years, or if you are reverting to something that is still embedded in every cell that has been turned off and then you have some damage and then it gets turned on again. But then it's already, it's kind of like a poet who's already written the poems. And then what you're doing in cancer is just pulling out the poems that have already been pre-written. Somatic mutation theory, you have to write them by selection on the fly. And that just doesn't make any sense because there's not time to do that.

So that's one way in which the atavistic model is much more predictive than the somatic mutation theory. And there are a couple of other details that I don't want to go into, but have a look at the chapter. It's called something about the atavistic model of the somatic mutation theory.

Aastha Simes: Are you familiar with Michael Levin's work at Tufts University?

Charley Lineweaver: Yeah.

Aastha Simes: So he has this interesting line where he says, you know, the interesting question to ask is not why we get cancer, but why do we have anything but cancer? Because I guess if you look at it from even the Richard Dawkins perspective, our cells should always be proliferating, right? Like our genes want to keep spreading and should be acting differently.

Charley Lineweaver: On its own part I disagree with that I mean to I mean it's very useful to have differentiated cells you have a liver you have a kidney you have a mouth you have a nose you have a throat the evolution of these things took we on the order of I don't know 500 million years since the Cambrian explosion for example 542 million years or so and the the evolution of these features and the regulatory mechanisms to stop them growing is something that is a normal part. I wouldn't say that those things should be difficult or impossible to understand as part of evolution. I would say they're a normal part of it.

So I disagree with the idea of, oh, the wonderful thing, the question that we should be addressing is, why isn't everything cancer? That would say, that's kind of like saying there's no reason for the Hayflick limit that I mentioned to evolve. And I said, no, there's perfectly lots and lots of selective reasons why in the past, if you did not evolve cell proliferation regulation, you died. You, you had to turn these things off.

Aastha Simes: I guess can the atavistic model help explain why we get cancer?

Charley Lineweaver: Yeah, yeah. Cancer is unregulated proliferation. Unregulated proliferation is something that A, we did two billion years ago, and B, we do very early on in embryogenesis. So that's why we still have the ability to go and turn over very quickly. However, more recently evolved, you have the regulation of that, which turns it off, and then you become a well-differentiated body that has cells that do not do that.

But when you have wound healing, you need to turn it back on and then turn it off again. When you have the lining of your intestines, they have to reproduce because you're always digesting the inside of your stomach and inside of your intestines. So it has to keep producing new cells because the older ones are damaged. So you have cell proliferation going on there in a place where you still need it. So also with your hair, your hair is growing, right? Your hair is growing and it keeps on growing.

Normal cancer therapy is what's called anti-mitotic. It says cancer is unregulated cell proliferation, unregulated mitosis. So we're going to give you drugs that stop cell mitosis. They're anti-mitotic drugs. But that's why your hair falls out, and that's why your digestive tract doesn't produce the lining again. That's why you feel terrible. So it has lots and lots of side effects. The reason why that's crazy, and we call that the cancer, attacking the strengths of cancer cells is because mitosis is something that cells have been doing for a long, long, long, long, long time. In other words, it is well embedded in cancer cells and every other cell. So to try to stop a cell from doing something that it knows how to do and has known for 3 billion years, is something that's very, very difficult.

So we think that the atavistic model has inspired a paper we wrote in 2014 in BioEssays called attacking the weaknesses of cancer, not the strengths. So in the atavistic model, the abilities of a cancer cells are its strengths. The weaknesses are the things that it has lost the ability to do. I'll give you an example. Maybe this helps. You know, Einstein, he died in like 1954 or something. He grew up speaking German and then he learned English later on in life. And when he was dying, you know, your brain, things go wrong in your brain. And then you start speaking. He started speaking German instead of being used to speaking English day to day. But then he started speaking German. So when something goes wrong with your brain, what does it do? It reverts to something that you had very, very early on, very early. So it's as if, like for him, German was the atavistic language and the new thing that he had learned was English. But when something goes wrong, like you're dying, you revert to something earlier and you're only speaking German and you can't understand English anymore. So that's a metaphor for what is happening to cancer cells. They forget what they have learned recently, like, hey, stop regular, stop proliferating. And then they revert to what they used to do that have deeper genes that are more protected and are older, 3 billion years old, rather than, let's say, 300 million.

Aastha Simes: So if we were to target the weaknesses and not the strengths, what would that look like?

Charley Lineweaver: Okay, so what you do is, if you can figure out, for example, let's talk about the cell cycle. If you Google cell cycle or Wikipedia, you will see all kinds of details about this phase and that phase and S phase and M phase and checkpoints all over the place. Now, there are, let's say, I don't know, 200 details about this thing that have been looked at. But what the atavistic model would say is, wait a minute, in this cell cycle, some of those checkpoints are involved in what's called the Hayflick limit to turn off the cell cycle when it's fully differentiated.

Now, what you need to know, now, the prediction of the atavistic model is that that cell cycle, something goes wrong with the checkpoints that stop it and it starts going around and around. Now, the atavistic model would predict, let's suppose there are 10, no, let's say that there are 100 pieces to this cell cycle. Let's say 10 evolved 10 million years ago, and then another 10, 50 million years ago, another 10, 100 million years ago, et cetera. So the atavistic model would predict that the more recently evolved ones get damaged. And then it kind of starts, oh, maybe I like this. I'm churning over more. And then it loses some more, and then it differentiates even more, proliferates even more, and gets more dangerous. That's why there's stages of cancer.

But if we knew, if we had a very good idea about the evolution of the cell cycle, and we could do this if people looked at the phylogenetic tree of life, compared our cell cycle to chimps, to mice, to, let's say, fish, and then to deeper and deeper. There are about 46 divergence points along our lineage. And by comparing what we have to what the other branches have, we can say, what was the cell cycle like of the common ancestor? Now, what's the cell cycle of the deeper common ancestor? What's the cell cycle of an even deeper cell? So you can trace the evolution and the changes of the cell cycle.

That's important because the prediction of the atavistic model is that the cell cycle will revert along those changes to what it was 200 million years ago, 500 million years ago, a billion years ago. And if we knew what those were, we could make predictions of what cancer does, what's wrong with the cell cycle of cancer cells. So that's a specific prediction of the atavistic model, but you have to make that prediction more precise and interesting. You have to do the homework of knowing what the evolution of the cell cycle was. And that seems like I haven't found the best paper on that. I wish I do. Who was the world's expert in the evolution of the cell cycle, who could then show us how these bells and whistles got added as a function of time onto the cell cycle. And then we could predict and then undo that and say, okay, we predict this will go, then this, then this, then this, then this, then this. And I'd love to be able to do that. But what was the question?

Aastha Simes: How do you target the weaknesses of cancer cells?

Charley Lineweaver: So if we're in the Einstein model, you start speaking in English. So if Einstein who's dying is one side, there's another Einstein over here, another Einstein, the normal Einstein can understand English. The cancer Einstein cannot understand English, right? So what do you do? You speak to these things in English. And all the normal cells will understand and they'll do what you want them to do, but the dying, the cancer Einstein will not.

Let's apply that to the immune system. Basically, very crudely, you have two types of immune immunity. You have innate immunity, the same type of bacteria as innate immunity, and pre-vertebrates have innate immunity. But more recently, about 500 million years ago, we have something called adaptive immunity. That's the basis of vaccination. So you get vaccinated and then essentially you have a system, adaptive immune system, that learns this stuff is bad. Whenever it comes, I have a bunch of T cells that are going to attack it. So when you get vaccinated, it kind of preps your system, the adaptive immune system, and then you have all kinds of police who are looking for those bad guys when you get attacked by those bad guys. That's the adaptive immune system, and it's recent.

So if the atavistic model is correct, then cancer cells should not, they should have a compromised adaptive immune system because it's more recently evolved. It should have the ancient innate system, but it should have something wrong with its adaptive immunity. So what do you do? Well, what we've proposed is that you give people a vaccination. You say, you know what I'm going to do? I'm going to give you a disease, but before I do, I'm going to vaccinate you to this disease. So I give you vaccines that's going to protect you from something that I'm going to give you later on. So now if you weren't vaccinated and I gave you this, you'd get very, very, very sick. Normal cells would have no protection. But since I'm vaccinating you, your body and any cell which can talk to the adaptive immune system will be protected.

Cancer cells, however, presumably, according to the atavistic model, cannot talk to the adaptive. They can't take advantage of this adaptive immune system. They only have the innate. So vaccination shouldn't help them. So you take a normal person, you vaccinate them, and then you give them a dose of something that you know will not hurt the normal cells because you've already got the dose right and you vaccinated them. And then the prediction of the atavistic model is because the cancer cells do not talk to the adaptive system, the vaccination will not be effective there, and that whatever you do, give them will attack the cancer cells preferentially because of this differentiation of normal cells have this protection and old cancer cells do not.

That's one example of attacking the weakness of cancer. We're attacking what it has lost and taking advantage of that loss rather than attacking its mitosis, which is its strength. And something like 90% of most cancer treatment is attacking the strength, they're anti-mitotic. That's why your hair falls out, that's why your stomach lining is so bad. This is very important to do, but I don't think anybody has looked at this very carefully, because what do a bunch of astrophysicists and astrobiologists know about cancer? I think that's pretty much some of the reaction we're getting.

I think people who are interested in the origin of cancer are taking our paper seriously, but so far, the people with billions and billions and billions of dollars who are just, you know, there's a hose of money from people who want to cure cancer. They haven't taken it seriously enough to try some of these ideas that we detail in our 2014 paper.

Aastha Simes: This is fascinating. Basically, you're saying, OK, cancer cells are really strong in the fact that they can proliferate. That's their strength. And with conventional therapies, like say chemotherapy, we're trying to stop them from growing, but they're so strong in that regard that we're failing there. Versus the weakness of cancer cells is that they've lost the newer quote unquote features that we have as humans. And they've gone back to the... They've gone back to the more, I guess, the parochial state. I know those terms aren't the best, but just for simplicity.

Charley Lineweaver: But notice that cancer cells de-differentiate. That is, when they first start out, they differentiate a little bit. That was they lose a little bit of the new stuff, and then they differentiate more, differentiate more. And essentially, they are de-differentiating to become cells that don't know where they are. But that's a little like cells before they start differentiating into the livers and kidneys, et cetera.

So anyway, it's a very predictive model, but you need to know what you need to know embryogenesis in a way very specifically because. That's why those genes are still there. You can say, well, wait a minute. Why do these genes of proliferation, why are they still in us? And the answer is because they are useful during some time during ontogeny, which is development. And that time is usually embryogenesis or wound healing. That's why they're still around after 2 billion years, because they've been used, and they're actively important. But after 5 trillion cells, they get turned off, suppressed.

What we need to know is what are the regulations that are responsible for the Hayflick limit? All over your body, when you get differentiated, then you get turned off. The mechanisms that turn that off are the things that go wrong that allow cancer proliferation. And so we have to figure out what exactly those are. But notice in the somatic mutation model, there's no motivation to find that out because you just say, oh, this happens, this happens, lots of mutation, selection, mutation, selection, and it turns into a proliferating hell. And so, hey, let's do anti-mitosis to stop this, but there's no, in the atavistic model, we say, wait a minute, this is so protective, this is so old, you're attacking the strengths of cancer. What you need to do is attack the weaknesses.

Another metaphor, for example, is I sometimes use this ridiculous metaphor, and that is cancer cells are protected, and normal cells are protected by a wall, but also there's a moat outside. And if cancer cells... You know what? I won't go there because I've forgotten. It was a metaphor I thought of. It didn't convince anybody, but it was a long time ago, so I'll stop. Ask another question.

Aastha Simes: Okay. So you mentioned wound healing a couple of times, and you said during wound healing, our cells start proliferating again. There's more mitosis. So could this mean that, say, when we have more damage in our bodies, our cells are again proliferating and perhaps when maybe there's too much damage or too much too much to fix um some of these cells once they lose the the checkpoints and the balances that they have for the Hayflick limit start going awry and these same cells that were turned on because of the damage basically now become cancer cells?

Charley Lineweaver: Well um yes and no. I mean, when you get a normal cut, the thing heals up, but there's a whole process that the cells go through of, you know, you have inflammation that turns the cells proliferating and then you get healing and then it scars up and then it's finished. It's okay.

But my wife had a bicycle accident and she was in a coma for a while and she had to be fed at the end by a PEG. I don't know if you know what a PEG is. A PEG is if you can't swallow food through your nose, then you put a tube into your stomach. And so you pour stuff in and it goes in your stomach. Now, when you no longer need that, when you can eat food regularly, they stop the PEG. Now the PEG is essentially, you have skin, they put a hole in your skin and then they can't, your stomach is there and then they kind of fuse it together. And so you can pour it right into your stomach.

When they pull this plug out, it's a little rubber donut that they pull out and then you want it to heal. What happens is that the cell, I guess of the lining of the stomach, for some reason they start to grow and they grow. It's a hole in your stomach and I'm not sure, maybe it's trying to heal itself, but it grows in undifferentiated way and it turns into what looks like a giant wart that won't stop growing. Now, interestingly, what nurses do in this case all the time is they put, I think silver nitrate on it that kills these things. And then the stomach cells get the idea that, hey, it's an anti mitotic thing, but it's also not cancer. It's just cells that have not gotten properly inflamed and then fixed it. And so they use silver nitrate to kill the things. But it's an interesting example of unregulated cell proliferation that I don't think you would call cancer because it's so easily stopped with silver nitrate and then it just heals up with normal scar and everything's okay.

Aastha Simes: Okay, so in those cases, they know that we need to proliferate for a certain purpose, but then they stop proliferating.

Charley Lineweaver: The whole process of wound healing involves proliferation, but also involves stopping to proliferate. And that's normal function of our bodies. And it's a good thing we have that. But you can imagine if you get a wound and then it starts to heal and then just keeps on proliferating. Then something is wrong with the normal mechanisms, and that's more analogous to cancer.

Aastha Simes: I think what I'm trying to get at is why do we get these cancer cells in the first place? Why do these cancer cells forget, lose their checkpoint imbalances for the Hayflick limit?

Charley Lineweaver: So obviously something's going wrong, and the things that go wrong can be any... There's many, many... Causes that are associated with damage to cells, for example, skin cancer, UV. So, when you have UV and have cells, something goes wrong and the DNA. Something gets damaged and then it doesn't get repaired correctly and then you get skin cancer. So, but there are many smoking tobacco, for example, you get lung cancer. So, there are many chemical causes UV, and they're also viral causes of cancer based, but the common thread is that something is wrong usually with the DNA.

And now, now that's important because DNA, um, you know, if you have a corporation and you start a company, you have very fundamental workers that have started the company and then it grows and grows and grows. And, and then you hire a summer intern. And usually if you have to have a tough time. It's like the last ones that they're hired. Those are the ones you fired. You don't fire the company president and the guys who are making the fundamental company run. You don't fire them now.

So cancer genes, I imagine, and I don't think this is crazy. There is a hierarchy of genes that your body tries to preserve and protect with more energy. And the newer ones are the ones that have just added on and said, oh, maybe they should protect it. I don't know yet, but the older ones that have been there a billion years or so, they are well protected. But when I say well protected, you can think of DNA being like a string. And you can imagine if you make a ball of yarn, and then you start to damage that yarn, the ones on the outside are the ones that are susceptible to damage or hitting or cutting or whatever, or acid or whatever. But the ones on the inside are well protected because they're wrapped around this thing.

Now that's a metaphor, but there's some truth to it because all your DNA is, there's many three-dimensional configurations that your DNA assumes. And depending on how it's wound around these histones and how it's packaged, something's going to be on the outside and more susceptible to the changes, the more susceptible to acid or UV or what all the other things. And if it were a ball of yarn, it would be on the ones that are on the outside would be susceptible, but it's a chromosome and so it has packaging that has evolved. And I assume that that packaging has evolved to make some genes more protected and conserved because they're more valuable to the fundamental functions of the cell. And others that are just kind of, oh, I evolved 100 million years ago and I'm a newbie here. And so there's a UV that hit me and then something goes wrong.

And so that at least is the hand-waving version of why new genes are more susceptible to the slings and arrows of outrageous fortune and other oncogenic chemicals or compounds than the more fundamental ones. There is a gradient of protection that is normal that has been selected for in the past that gives a gradient of protection to more protection for the older ones, less protection for the newer ones.

Aastha Simes: That's really fascinating, honestly, because, yeah, the older ones, if you think about it, have been with us for decades. Way, way many more years, like billions of years.

Charley Lineweaver: And you better protect the boss of the company and the people who know how to make the whole thing work. And summer interns, you know, who cares? But if that's the case, the company then reverts to its atavistic state without its summer interns and the other people it hired in the last year and reverts to what it was before they started hiring those others.

Aastha Simes: Which makes me think, and I think some of this is Nick Lane's work as well. How did we go from becoming unicellular to multicellular? I don't know if you've looked at that.

Charley Lineweaver: Well, so you want to know, so how did we go? Well, first you take one cell and you have another cell and then you attach it to that cell and you make them stick and you evolve something that makes them stick. And also maybe they say, why do I have an advantage? There has to be some kind of advantage to being in a, for example, there's lots of, actually, there are lots of examples of Volvox, for example, of eukaryotic cells that are individuals.

Actually, one of the coolest things is some amoeba, slime molds. Have you seen slime molds? Slime molds are great. They're individual cells, and they're knocking around, eating, doing fine things. But then when you starve them, what they do, they come together and they form a stalk, looks like a little mushroom, and then it forms this whole body. And it's the weirdest thing to see these single cells that for all the life of them, they look like individuals that don't care about each other. But then when they starve, they say, ah, and they get together, they swim, create a stalk, and then they make spores.

What's really cool about this is the cells that form the stalk don't get to reproduce. They're kind of like the somatic cells that don't reproduce, but at the very top, they have spores, and these are your sex gametes, essentially, and then those are the cells that do get to reproduce. So it's a really weird, how in the world do some cells sacrifice their life to produce the stalk to then allow the cells that have it different genomes. I'm not sure how different. Maybe it's not that different at all. So it's more like a monoclonal body. But in any case, if we make the assumption that these single slime mold cells have different genomes, then essentially you're talking about altruism evolving for group selection that provides this stalk that you need in order to get your spores further away from this terrible environment in which there's no food.

Aastha Simes: Interesting.

Charley Lineweaver: So outside of the origin of multicellular. So there's some things that multicellular things can do that single cells cannot do. And I imagine, I don't know if you heard of stromatolites. These are bacterial layers. If you go to Shark Bay in Australia, you will see these things. And they're essentially they're bacterial mats. And you could ask the question, are bacterial mats, multicellular things? Well, they're, they're, they're one species here, another species here, another species here. So there's layers of different species and they're all working together. It's more like an ecosystem.

And, uh, well, I guess at some time in the past, about, about 600 million years ago these cells got together and they said, hey, we can do things together that we couldn't do individually. Kind of like that stalk in the, uh, the slime mold case. And, uh, or creating a stomach or creating a brain or creating eyeballs. There are a whole bunch of wonderful things that multicellular creatures can do that single-celled creatures can't. And if that's the case, you can well imagine that there were reasons that these things got together and gave them ability to do things that they couldn't do individually.

Aastha Simes: So outside of the, say, implications of attacking the weaknesses of cancer and maybe developing this vaccine that does so, what are some of the other implications of this research?

Charley Lineweaver: Well, the other implications are it's very, very predictable because if you understand how your ancestors evolved from 4 billion years ago till today along the lineage that led to us, this atavistic model makes predictions about what are the weapons that cancer, what are the strengths that cancer has and what are the functionalities that it will lose as it progresses. Remember, it's not just losing the new ones and keeping the old ones. This whole thing is a work in progress in the sense that as it reverts more and more, it's losing more and more functionality and reverting to earlier and earlier functionality because that functionality is no longer repressed. Because the repressors are something that evolved afterwards and they are getting damaged for the reasons we talked about.

So the question was, what else can we, what else? These are, so these are predictions, but usually you want to know some therapy. Another example that we talked about in our 2014 paper is, you know, there are drugs that people that are given to people. And who have cancer, and there's a problem with it because they develop multiple drug resistance. So you give them a drug, an anti-mitotic drug usually, and normal cells have transmembrane proteins that get rid of garbage. So you have a picture of a cell, picture a hole in the cell, and there's a guard on either side, and these are called ABC, ABC cassette, what's it called? ATP, I forget what they're called. Anyway, they're called ABCs. Essentially, they're garbage collectors that take the garbage from inside the cell and push it out.

Now, there are a whole slew of them. There are probably hundreds of these, and each one has some advantage. Some can remove garbage A, you know, cans, and the other people remove paper or something. And they're specialized with different things. And so our prediction of the atavistic model is that the newer garbage collectors or garbage removers are the ones something goes wrong with, but the older ones are still active. So if you could figure out what is it that the new ones remove, then that's, and the cancer cells cannot remove them as efficiently as normal cells because they no longer have access to these newly evolved garbage collectors. So they're ABC, just call them ABCs.

And so this is an example of a system that has evolved to clean the cell of its garbage in many, many, many different ways, hundreds of different ways. So when you give drugs to a cancer patient, these drugs are seen as garbage and these cells can get rid of them quite effectively because they have these old ones that are still working because they're more generic drugs. And they're not as specific, I guess, as they're less efficient. Well, I would say that they are less, they're more generic in that they take, hey, this looks like garbage, I'll throw it out, rather than in the newer ones, oh, this is paper, I'll get rid of it. Oh, this is cans, I get rid of it. Oh, this is glass, I get rid of it.

So that's a little bit of another metaphor in which there are more refined and more specialized ABC garbage removers that, in our prediction will the newer ones, the garbage, the paper, the glass and the plastic, those ones are no longer functional. The generic ones still working in cancer cells. And so what you have to do is provide the drugs that are the ones that can no longer be removed as effectively. In other words, target the weakness of the cancer. What is the weakness? The weakness is it no longer has the paper, plastic, and glass specific removers, but it does have generic earlier ones that are effective at getting rid of the drugs that are being administered. Why? Because those drugs are taking no account of the type of differentiation of the ABCs that I'm just trying to describe here with this metaphor of paper, plastic, and glass. Do you see what I'm talking about?

Aastha Simes: Yeah. Yeah, I think so.

Charley Lineweaver: Again, new stuff doesn't function anymore in cancer cells. Old stuff does. That provides a lever arm, which if you are aware of that lever arm, you can provide drugs that will not as efficiently get removed by the older cells, which no longer have access to the more newly developed garbage removers.

Aastha Simes: Interesting. So when people think cancer spreads, it's not that more cells are necessarily becoming cancerous. It's just that the cancerous cell is spreading to all different parts of the body because it's proliferating in an unregulated way.

Charley Lineweaver: Well, the wonderful thing about metastasis is that these cells, these cancer cells, have to start at the primary location. Then they have to get into the blood system. So they have to get into those arteries and then they have to go and then they have to get out again. These are wonderful abilities that not, you know, you'd think how in the world do cells know how to do that? And that's because all the cells in your body know how to do that. Why is that? Because some cells during normal functioning have to do that.

For example, your immune cells, they have to be produced one way, like your bone marrow or something. And then it has to learn how to get, into your blood system, circulate, and then get out of your blood system and do its job. Now, those are all of the wonderful, I don't know, enzymes that are involved in that type of transportation and migration, and you have to camp out, and then you have to find a place to stay for the night. These are the things that cells know how to do because some cells have, actually, all cells have the same DNA, right? It's just which DNA is turned on.

And so if you are turning on genes that have been selected for in the past to enable you to do that, the cancer cell is reverting to an ability that all cells have, but it's usually suppressed in most cells. And it's not suppressed in those cells that just normal function is to go into the blood system, move around, get out of the blood system and fix things. And for example, wound healing, that's something that happens, right? You have to get your immune system cells that, ah, there's a cut there. And so you have to get cells. I'm not sure where they're produced. I think inside your bone marrow, then has to get into your blood system and go to the wound and then get out of the blood system and then do its, whatever it is the cells say, reproduce, reproduce, come on.

And so the prediction of the atavistic model is that there is no ability, no functionality of cancer cells that isn't already present in normal cells. We're not inventing anything new. Nothing new is evolving here. It's just reverting to functionality that is already there and used during some time during embryogenesis or wound healing. That's not, somatic mutation theory has no limitation like that. You there, you say, mutation, mutation, mutation, mutation, and then selection, and oh, by the way, whatever you're coming up with is, you're not coming up with anything new.

So that's the prediction of the atavistic model, and that is that cancer cannot do anything new. Somatic mutations, they should, hey, there should be new stuff all the time. And there should be no reason that there should be any hallmarks of cancer. And there should be no reason that my cancer should be the same as your cancer. And yet, there are many, many commonalities between liver cancer or lung cancer or skin cancer between patients.

Aastha Simes: So, but if it's reverting to this functionality, which it already has, which is proliferation, I mean, the functionality that our cells originally had was regulated proliferation because of the Hayflick limit.

Charley Lineweaver: No, it's not regulated in the very beginning. Remember, you start out as one cell and now you're 50 trillion. It was very unregulated, I would guess. Well, it's regulated in different ways, but it's definitely not turned off. There's nothing anti-mitotic about it, but the Hayflick limit only comes after about 40 divisions. This guy Hayflick, what he did was he took human cells and put them in a petri dish, and then he said, whoa, look at them, divide, divide, divide, and then they stopped dividing. And they did it again, they stopped dividing. And so after studying this under controlled situations in many different ways, he said, there's a limit to how many times a human cell will divide. And that's now called the limit.

And that's the genes responsible for that are something that needs to be looked at because some, those are the ones are part of the ones that go wrong when you get to this cell cycle, just unregulated going round and round and round.

Aastha Simes: Okay. Yeah. Interesting. So it's like, okay, we didn't have this regulation, but at some point, this Hayflick limit regulation came in, and that's when we stopped dividing. But now the cancer cells are losing the Hayflick limit again.

Charley Lineweaver: Yeah, the newer version, I'm sure there's layers and layers responsible for turning cells in different parts of your body off. For example, you have to maintain some cells without a Hayflick limit because you need to replace this hair, you need to replace the skin, and you need to replace the linings of your GI tract. And so there you don't want a Hayflick limit at all in the normal functioning human body. And so that has to be there. You cannot have a Hayflick limit. You know, cell proliferation is very useful at certain times in certain organs, and that's normal.

Aastha Simes: Yeah. So I know you touched on this briefly already, but why doesn't this research get more attention?

Charley Lineweaver: Well, I think one answer is we're astrophysicists and astrobiologists and we know nothing about it. I think the other thing is it's kind of, it's based on four billion years of evolution and specifically the evolution of multicellularity and doctors are not trained in evolution. And also they're trying to get, as I mentioned earlier, they're trying to save lives, as you understandable, and so they don't have time for theory.

But you could say, well, wait a minute, aren't there people all over the world who are trying to find cures for cancer? And that's true. But I would guess 98% of them are doing what I call the whack-a-mole, and that is anti-mitotic research attacking the strengths of cancer because it makes sense. If it's an unregulated mitosis, you have anti-mitotic drugs. That's just clear as clear to everybody, but it's wrong, I think. And that's why we wrote that paper.

I think we've gotten a lot more attention in the Chinese community. I noticed that a lot of people are citations in Chinese oncologists. There seem to be more open to this idea than a lot of the more established American ones. We are getting more attention, but mostly from theorists who like to think about the origin of cancer rather than the people who are getting the big bucks to take a bunch of cancer cells and put a thousand different chemicals on them and see which ones stop proliferation. And then, OK, that's a new cancer drug. That's just that's what I call it. Whack-a-mole research.

Aastha Simes: Yeah. Do you know if any researchers in China are trying to develop drugs or vaccines based on this atavistic research?

Charley Lineweaver: I don't know, but I do know that several people who are thinking they're more theoretical, trying to understand the origin of cancer, are taking our work more seriously. I mean, there are some people in a couple of people in France, a couple of people in the US but the big centers of cancer are very married to this somatic mutation theory and anti mitotic drugs. And so they don't take it seriously.

I don't, uh, a couple of people every once in a while ask me, hey, has anybody taken these ideas seriously and trying them out in specific cases? And the sad answer is I don't think so, but, uh, you know, I'm not, I mean, if somebody asked me how to do that, I could go through specifically what the evolutionary, what the evolution of a specific, like the ABC proteins or the cell cycle, you'd have to figure out what, how that evolved, what were the stages, and then predict what would be lost in cancer. And then that tells you what the weakness of cancer is.

And for many, many systems, metabolism is, the Warburg effect is another example that can be taken. Uh, for example, uh, cancer cells don't do they, they do a form of respiration that's called, uh, aerobic glycolysis. In other words, they use a very inefficient way of respiring, even though there's oxygen present. And so, uh, what you can do is, is put more oxygen there, uh, to if, because cancer seems to like hypoxic environments. And so that's the reverting to an earlier form. Uh, also embryologically or earlier, because your, your blood system is not fully developed yet. And you have a goal of cells that is doesn't have access to as much oxygen as you have later on when you have all these arteries everywhere.

Uh, anyway, there are many, many lever arms that you can identify the weakness of cancer cells under this model and they can be used and therapies can be developed about them. But so far, no one has taken it specifically seriously enough to do that. They're still anti-mitosis, anti-mitosis attacking the strengths of cancer.

Aastha Simes: Well, I hope this podcast spreads the message to more people and maybe someone watching this could take it seriously.

Charley Lineweaver: Uh, well, I think a lot of people who are not specialists can take it seriously. They could say, oh, that makes sense. And they like, you are nodding your head right now, but you probably don't know that much about provide doing cancer research. But so we have convinced lots of people who are not getting billions of dollars to try to develop new drugs or to develop new cancer therapies. But the people who are getting the billion dollars, I don't know of anybody who's listening.

Aastha Simes: Well, is there anything else you'd like to add, Dr. Charley Lineweaver, before we wrap up?

Charley Lineweaver: Well, for people who want to know more, just Google my name, Charley Lineweaver and google Paul Davies' name, and you will see, let's say, about a dozen papers that develop the specific aspects of this. We wrote earlier papers as early as like 2011, and we've been writing a paper every other year, so developing the idea more specifically. In the most recent paper, we talked about how cancer is not just a one single reversion to the past, but rather an ongoing process of progressive reversions. It's sometimes called the sequential atavistic model, and that's the paper we wrote. I can recommend that. And read about it. And if you have a friend who's getting a billion dollars to do cancer therapy, see if they are open minded enough to try to use, I don't know, say, 10 million of the billion dollars on and trying this attacking the weakness strategy that we've discussed in most detail in 2014.

Aastha Simes: I'll also link to your website and some of the papers as well. So thank you so much. This has been wonderful. And I do think your research is really fascinating. So thank you.

Aastha Simes: If you enjoyed the podcast, you might also enjoy my newsletter, livelongerworld.com, where I share practical longevity tips and also upcoming releases of my podcast episodes. Thank you for listening and I will see you next time.

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