Welcome to a topcast and to a special presentation. Today I'm not delivering a soliloquy, nor am I even interviewing someone else. Today I'm handing over the podcast wholesale to my previous guest, Charlie Lineweaver. Charlie is a cosmologist and astrophysicist by training. I've mentioned many times before on the podcast, but he also works in the burgeoning area of astrobiology. And he's now become an expert in evolutionary theory. And as we will shortly hear, the theoretical underpinnings of the causes and possible paths to new treatments for cancer. This topic, which is Charlie Lineweaver and Paul Davies theory of cancer, known as the Atavistic model, has been published in a number of papers available at Charlie's website and elsewhere. This here is a lecture which Charlie delivered recently, and which can serve as a kind of technical introduction, if you like, to his ideas, which are an alternative to the prevailing theory of cancer, which is basically just taken for granted, which he will explain and compare and contrast with his own. He's going to explain this new Atavistic model and how it is testable, what predictions it makes, what treatments in theory would flow from taking this new theory of cancer seriously. Now, I'm promoting this because I think it is important work. It's part of our unbanned capacity to make progress and correct errors, especially deep theoretical errors which may still exist and persist throughout medicine. We should expect them to, as we should expect them to, exist throughout the rest of science as well. But this, if you're interested in living forever, or just as significantly lot longer than what you're presently predicted to be able to, given we're all going to get cancer at some point, living long enough, we should want to support the people who are working in iconoclastic new ways in order to challenge orthodoxies, I would say. Not just for the sake of it, but because they might just very well have a good explanation, and when you listen to Charlie talk as you will hear, it sounds like a good explanation. Now, of course, it needs to be tested, other people need to do the work, they need to check his peers, in other words, people who also understand this work at the technical level, need to be able to dot the eyes and cross the t's, so to speak, and to do the experimental work, and we'll get to that towards the end of this lecture today. This particular podcast here, my episode 216 of Topcaster you're listening to right now, Astrobiology and Cancer, can serve as a supplement to the wonderful conversation Charlie had recently with the Live Longer World podcast, where he talked about some of the stuff, but today he's going to go into greater depth, more length, and more technical stuff. There are slides and some questions from the audience as well in part of my podcast here today, the lecture, and if you're listening on audio, you'll get most of the gist of what is going on, but Charlie is referring to slides, which I'm going to put up on the screen in addition to him wandering about the podium. Or the stage, so to speak. So these new ideas are subtle and technical in places, but also thrilling in the context of if you're interested in the topic of longevity, and just the general way in which Evolution by Natural Selection is itself a fascinating topic. This is episode 216 of Topcast, and as always, it's being delivered totally for free as a public service in large part, but in particular here with this particular episode, I think it's critical that this specific theory needs more attention paid to it, rightly or wrongly, as it turns out, whether or not it's going to actually help us, or whether it's going to just be a footnote in the history of research in cancer. Every avenue is worth pursuing, and this is one new way which some serious physicists might be contributing to the conversation around oncology. So without further ado, over to Charlie Lineweaver to explain the finer points of the Atavistic Theory of Cancer. All right. All right. Can you hear you in the back there? Good. All right. So yes, thank you for that introduction, Brett. Thank you. So how are astrobiology and cancer connected? And how does an astrobiologist get interested in cancer? And of course, there's a connection between cancer and longevity. And this is the type of thing as a cosmo biologist we make all the time. It's not all the time, but anyway, here's the Big Bang, hydrogen helium, making different stars, big stars go boom, produce these elements. Those residual things called oxygen and carbon, nitrogen, things that weren't producing the Big Bang, form a planet, somehow life gets started, and then recently we've been able to draw the whole tree of life on Earth. This particular tree does not include viruses that I would advocate that they should. Anyway, so there's some colon cancer right there. So 1995, just five years before your story, the first planets were detected orbiting other planets, orbiting other stars. And then in about 2001, there was a problem at USW, the administrator said, "You know what? We need more people signing up. We need more bombs on seats in the physics department." And the X files were very important back then. The students love the X files. And they said, "The truth is out there." And I said to myself, "The truth is out there. We know much, we're astronomers. We know much more about whatever truths out there than these Hollywood producers of people falling in love." So we said, "Well, let's start a course called R.E. alone. That'll get some bombs on seats." And so we did a new course called R.E. alone, or the search for life elsewhere in the universe. And that's at the University of New South Wales in Sydney. And so part of this course was we took, it said, this is a movie. So there's a one frame, two frame movie. Here's what the sun looked like about 4.6 billion years ago. It's an over density and a molecular cloud in the galaxy. And then somehow this happened. This is a kangaroo. And so this transition from this to this, a cold odorless gas to a life form, happened on Earth. And we want to know has this transition happened elsewhere. And so that was the thing we were talking about. So that involves trying to understand the entire 4 billion year history of life on this planet. How did it get started? What happened after 100 billion? What happened in half a billion years after the formation of the sun? You have to learn all about the history of the Earth, history of water, the atmosphere, and life. And interestingly, well, here's Paul Davies. So he had written this book called The Fifth Miracle about the Origin of Life and how possibly were Martians. In other words, life might have gotten started on Mars first and then migrated to Earth. That's still a plausible hypothesis. But this book is about that. I saw that and I said, you know what? Let's have him as a guest lecturer. So I invited him to give a guest lecture. And he did. And turns out that we had many common interests. And here's the, matter of fact, here's the first picture from his lecture in, I don't know, in 2002, I think, 2003. So that's what I looked like. Here's his somebody 22 years older. Still alive. All right. So we got the talking and we had many common interests. And one common interest was cosmology. He was a mathematical cosmologist. He knows an awful lot about black holes. You have the question about black holes as Paul. And I was an observational cosmologist. I was analyzing the data from the Kobe satellite, the differential microwave radiometer. And that's what got George Smoot, my supervisor of the Nobel Prize in 2006, I think. In any case, Paul knew of my work in the cosmology. And theorists always like to talk to people who are doing with data. And so we got to talking about almost everything. And so we started writing papers like black hole versus cosmological horizon entropy. Tamara Davis was my first PhD student there. And then we wrote this paper on the second life on earth and shadow biosphere, trying to find life on earth that biologists do not yet know about. Why? Because it's so small, and has different templates and different sequences that are not, cannot be found using the templates that people do. Anyway, so then just to put it in perspective, the human genome project finished in April of 2003. Now that project led to a whole bunch of technological advances that enabled sequencing of genomes. But it wasn't just human genomes. Matter of fact, this is the speed at which the technology to make the sequencing improved was incredible. And so, but, and then they found out, okay, there's about 20,000 genes in the humans, and that's about 2% of the genome. These are the genes that are translated into proteins. But that enables, once you get this gene sequencing, that enables gene sequencing of other life forms. And that enables an increasingly precise phylogenetic tree of life. And that really helps to understand what has happened to life as a function of time, not just on a .8 billion year time scale. I'll show you even a bigger tree in the next five. But the point is, you can get the gene ages. Each one of those 20,000 genes, you can get their ages based on gene homology. How does that work? Well, you may have heard that here was a chimp, here's a human, and we have a common ancestor about six or seven million years ago. We know that because we have approximation, we have approximations of how quick the molecular clocks tick. And so, if somebody says we involved from chimpanzees, it's completely stupid, because we evolved from that point there, which is the common ancestor of chimps and humans. If you say you evolved from chimps, you're saying chimps didn't evolve, we did. And that's just stupid because we can now look at the exact sequence of genomes, the exact sequence of DNA in a chimp, and we can end the one as human. And we can see that both have evolved about the same amount, as you would expect, if they diverge at the same time and then evolve separately. So, the idea that chimps haven't evolved and we have is just stupid, throw it out of your head. Okay, so you can do the same thing with a mouse. If you have a dog, the common ancestor of you and your dog was about 95 million years ago. And we know that because there's lots and lots and lots of stuff, probably something like 92% of the genome of your dog is the same as yours. But then there's this 8% that's different, and that's because you have diverged 95 million years ago from it, the same with dolphins. All right, so you can play this game for anything because we get all these sequences from all these living creatures. The point that a big mistake that people make is these are your ancestors. So, we can know what this sequence was here. Why? Because we know this, we know this, we know we have gorillas, we have orangutans, we have three species of orangutans, two species of gorillas, two species of chimps, and we can slowly back, back, back, go further and further and figure. And we know when we create this tree what these genomes approximately were. Now, for example, jawless fish, you know how many jawless fish there are? There are, I don't know how many either, actually there are quite a few, how many sharks? There are many, many sharks. All of those have separate lineages that have been ignored in this tree, simply because I wanted to keep it simple. But those extra species allows you to reconstruct what was here, what was here, what was here, what was here in the same way that we're doing here for humans. This is your humans' lineages, this is where our ancestors live. This is phylogeny. And so, is it clear how gene ages are determined here? You find a gene here and then ask, is it in the chimp? If it's in the chimp, end humans, it's at least 6 million years old. If you find it also in a rodent, then that gene is at least 80 million years old. If you find it all, also in a kind of germs, then it's 700 million years old. That's based on gene homology. Homology's just a fancy term for common, they had a common ancestor. That's what gene homology means, that the two genes you're talking about have a common ancestor. Okay. You match them by sequences. Actually, you identify what a gene is and then look for that sequence in the other genome. And then you say, well, then you just match them. There's a lot of details, in a lot of mistakes you can make if you do it wrong, but it's been going on for quite a while now and I have a lot of confidence in it mostly. Okay. So this is 0.8 billion years. Now, this is interesting. You know, dutar stones are here. We're dutar stones. That just means that when you were an embryo, you had a hole and that hole became your butt and the second hole forms became your mouth. Stole is mouth and so protostomes are like these insects here. The first hole in the blast, it turns into their mouth. That's why it's called protostome. The first hole is the mouth. We're dutarous stones. The second hole is the mouth. That's a very big, it's kind of like what we are is just a gastrointestinal tract. And when you form a tube, one tube can be the mouth and one is the butt. Or you can do it the other way. And that's this, that's a symmetry breaking that happened among these organisms about 800 million years ago between dutar stones and protostomes. And there are all kinds of interesting details like that. And, but also based on this, you can see, you know, you know, we're an ape. We're a primate. We're a placental. We are a mammal. We're an amniot. We are a lobed thin fish. We are a bony fish. We are a george, etc. So you may think that you're not a fish. If somebody asks me, are you a fish, I say, yes, I'm, of course, I'm a fish. Fish, fish is everything that's from here up. All of these are fish. All of these are primates. And all of these are dutar stones. So everything above this is a dutar stone. So if somebody asks you, are you a fish, you should say, yes, Charlie told me, based on this tree. Now, and another interesting thing is these are your ancestors. This is where your ancestors were. And we know their genome, the way I've just just described, these are your cousins. They're not your ancestors. They're related to you, but they're not your ancestors. That's a very important distinction. If you know anything, if you learn anything about this, this is ancestors here, cousins here, cousins are alive. These are... Okay. Now, so that tree was 8.8 billion. Now I'm going to show you one, same thing, with 4 billion. And here it is, here are your ancestors, here are your cousins. Now, here we're going all the way back to bacteria, D-pan, tach, eschar. These are types of archaea, for example. Here we have fungi, about 1.2 or 1, amoebas, plants. You just... You study plants, right? Well, our common ancestor with plants was about 2 billion years ago. Okay? So you have a common ancestor with plants, 2 billion. You look out there and say, oh, there's my cousin. We had common ancestor 2 billion years. You look at a fungus, 1 billion. You look at your dog, 95 million. There are these dates that are beautiful because they have been recently found due to basically the technology that was invented with the Human Genome Project. So none of this, what I just told you, plays any part in the education of an oncologist. They do not know this. This is new information only since 2000. Doctors... That was one of the first things we learned when we were studying astrobiology. We got a little bit interested in cancer. We started talking to oncologists. They knew nothing about this. They didn't know when multicellularity originated. And I said, cancer is a disease of multicellular organisms. They don't know anything about multicellularity. Something is missing here. Something important is missing. All right, so I explained how you got these gene ages. So essentially, every one of those 20,000 genes, you can get an approximate estimate for how old it is. That means some genes are new, some genes are here, some genes are here, some genes are here. So if you... at the crutus level, you can say old genes, new genes. Ancestors. And now, phylostratigraphy is the fancy name for what I just described, getting the dates on the ages of genes. Gene age is based on gene homology. All right. Another thing I wanted to point out is that in 1816, Heckle was a... Ernst Heckle was a very big fan of Darwin. And he loved it so much. He came up with this saying called, "untogeny recapitulates phylogeny." "untogeny" simply is a fancy word for development of an individual. Phylogeny, we just talked about the phylogenetic tree. So he's saying that when he... what he did was took a picture of a human fetus, a chicken, and a fish fetus, and then he looked at... oh, look at how similar they are in the early stages of embryo genesis. And then he said, "Oh, look, they're starting to diverge. They're starting to diverge." But the point was that the older they got the more divergent they were, the younger the embryos that were being compared, the more similar they were. That's what ontogeny recapitulates phylogeny means. There's a giant debate about what exactly Ernst Heckle meant, but a lot of modern embryologists, if you mention his name, they will yell at you. So you should refer to these papers which are more acceptable to modern embryologists. You have to be careful when you say this because you will get slapped as we wear several times. Okay, anyway, the reason I say that is because here's a paper from 2007 saying, human embryonic fetal and adult hemoglobin are different. That means when you are... Because I haven't read the 1866 book by Heckle. What they hate is they think Heckle said, "When you're a human, first you turn into your fish, then you turn into an amphibian, then you're a reptile." So they think that Heckle said, "You were an adult version of a fish," and then became an adult version of a frog rather than saying, "Your earliest stages of your embryology were very similar," and then they diverged as you go towards birth. And so they think that Heckle thought this adult frog, adult reptile, and that's just stupid. I don't think Heckle said it, but I shouldn't say that because I haven't read the 66. But what that means is, and this is so interesting, that human embryonic fetal and adult hemoglobin have different subunits. What that means is, before you were born the first week, the second two weeks, five weeks, you were expressing hemoglobin that your ancestors expressed, but adults no longer do it. It's a little like a miniature... It's a more important version of lactose intolerance, right? When you're a little kid, you can tolerate lactose, but usually in mammals, that goes away. Because if you turn adults, you don't suckle anymore. But then they invented cows. We needed lactose to help some tribes, and so you had mutations among peoples who had animal husbandry, particularly milk from cows, and then adults learned how to do it. So similarly, so when you look at normal hemoglobin, human, they're different from fetal ones. And this is true almost in any aspect of your physiology, you want to mention. If you go back, now you can't do this with humans, but you can do it with mice. And so you go back, you gotta go up to one cell stage, a hundred cell stage, and look at exactly what is the physiology that's going on inside those cells as a function of post-fertilization. You will see very similar things that you see in the ancestors. And that's kind of weirdly interesting, but it seems to be a very strong pattern, and this is just one paper from that. So then about the same time, this guy Douglas Hanahan came to ANU. That's the Australian National University. I've moved from University of New South Wales to Australian National University. And he was one of the people who became known for a paper on cancer hallmarks. Now this was a very, almost a revolutionary paper, because up until this time, cancer authorities would say, "Oh, what is cancer?" And they'd say, "Oh, it exists." And sometimes this and sometimes this. It's very complex. And so there, it's not one disease, it's a million of them. But these guys who, after a cancer conference with Hanahan and Weinberg, took a long walk and said, "You know what, this is not, we're kind of fooling people by this. We're misleading them, because there are characteristics that we can identify that are common to all cancers in more or less, not exactly, but more or less." And so to see that pattern, you need these expert guys. And so these are the hallmarks of their 2000 paper sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death. So these were the hallmarks. And I asked him, is there any ability that cancer cells have, because to do all this bad stuff they're doing, it takes a lot of organization. Cancer cells are not just some anarchic cells, they're well organized, they're even out competing your own cells in your body. So that takes abilities. But it's not the abilities of normal cells. But in some way it is, because normal cells also have those abilities. Now remember, every one of your, well not everyone, but the vast majority of your 30 trillion cells have the same DNA. The only difference between a liver cell and let's say a brain cell is because when it was, when there was a differentiation cascade, it said, okay, turn on one, turn off two. And that led to a divergence in their fates. And then enough of those changes. And then you turn one into liver, one into lung. But all of that information is still in each of those cells. So that's important to know. So is there any ability that cancer cells have that is already present, that is already present, as an ability of normal human cells? And when I say normal human cells, I mean during the entire process of development or ontogeny. I say that importantly because there are lots and lots of things that your body did and lots of proteins that were turned on when you were one day old, two days old, a week. And we don't know very much about that because unethical to just cut up fetuses as you will. So you have to do it with mice. And to the extent that they've done it with mice, you can see that there are a lot of things that are old, these old ways of old proteins, old genes, that are active in the earliest epics of embryogenesis. Okay. And so this is why I asked him, is there any ability that cancer cells have that is not already present as an ability of a normal cell? He said, well, hmm. In fact, I just wrote him a letter last night asking the same question. The reason I asked that is because in the standard model of what is cancer, you will hear over and over again. And sometimes they just assume it without saying it, something called somatic mutation theory. Now what that is essentially somatic is there are soma cells and then they're germ cells. These are the asperm and eggs are your germ cells and everything else in your body is a soma. And this has been programmed to die because what do you do? You're the protector to pass on those germline cells. I should say that that aspect only comes along about two billion years ago when there's sex is invented. Before about two billion years ago, there was no sex and there was no programmed death. There were no somatic cells that were there to protect the other cells. Why? Because they were single-celled eukaryotes. Only when you start having colonies and then the colony started doing good things to protect the passage of those genes, then the dividedist division between the soma which were disposable. And this is a, I think a German scientist who came up with this idea of disposable soma. His name is Weizmann. You can read about him in the embryology textbook or evolution textbook. Anyway, this answer says, now the reason I brought this up is because in somatic mutation theory, it goes like this. Things are damaged. You have viruses or carcinogen, tobacco, some kind of UV radiation, you're damaged somehow. That damage produces a lot of genetic variation inside your body. These are your own cells that are damaged in some way. And then that variation is then selected in a normal process of Darwinian evolution. In other words, the things that can't survive just die and the things that can survive survive. And then again and again and again, they get more damage, same thing, same thing, same thing. So you have a process of more or less standard Darwinian evolution which is going on inside your body as cancer is progressing in your body in the way of just describing. But notice when you say it's just mutated and then selected, you could produce new stuff that way. That's how new things evolved in the first place. But it took tens of millions of years for any little particular, hey, that's a nice trick, that's an adaptive, any adaptation like that takes a while because you have to kill a lot of things that didn't quite have it. Now there's, they're proposing that this process of Darwinian evolution goes on inside your body among the cancer cells because they're getting damaged, they're mutating in and selection. In our, so if that's the case, then you should imagine that every once in a while, a new thing would come out of that. But no, new things don't come out of it. You always get, you revert to these hallmarks. They think the cancers in, revert to these hallmarks because of the selection pressure that's so strong that makes these converge. Now if you get cancer, if I get cancer, our cancer will diverge, will converge on these hallmarks. Yours will have, you know, a lot of this, a lot of this, and mine will have a lot of this, and they'll be similar in many ways. And that's how they came to this hallmarks in the first place. Any questions? This is all clear? You believe me? Okay. All right. I'll move on then. So Douglas Hanahan says, now why that's important question is because if cancer cells cannot do anything new, then everything that enables the ability of cancer cells to do what they do is already in the human genome. It's pre-existing. So if you have variations that are pre-existing, you're not talking about Darwinian evolution with random mutations. You're talking about reverting to something that you already knew how to do, but had been suppressed. So let's move on. Okay. 2010 was this paper. This is a Croatian phylostratigraphy. If you look up this guy in wiki, you'll say, he invented phylostratigraphy. That's essentially taking these different stages, these different nodes, and then examining, well, by that time they had cancer genes. And so using the cancer genes that had been identified in tumors, biopsies, he then said, which, how old are those genes? And he said, okay, look, these are down, the ones that are down here are under-expressed, then the ones that over here are over-expressed. So you can see there's a definite signal in this data of, as you get older and older genes, which are right here, they get more expressed in cancer. Yes? So cancer genes have been identified as being old. Here's old and here's young. Now, notice that this is kind of different than the tree I showed you, because, look at this, he did the strata, and this kind of misleads you to think that all these strata have equal amounts of time between them. But no, this was, he was did this at a time when we didn't know exactly the time differences between the strata. But he just proposed it like this anyway. And so the crude, I guess it's more than a crude result, is that the newer genes are under-expressed in cancer cells, the old genes are over-expressed, just like I've been telling you. So, then, the year later, we said, you know what, this is all adding up to a picture that is identifiable as cancer tumors as metazole 1.0, tapping genes of ancient ancestors. This is the first paper we wrote about the atavistic model. And it says, "Our proposal explains the paradoxical rapidity with which cancer acquires a suite of mutually supportive, complex abilities." That's just a fancy term for cancer hallmarks. And these hallmarks are acquired very rapidly, as opposed to the 10, 20 million years, it would require if this was just normal Darwinian evolution. So, you're just reverting to something that's already there, and in fact, you used to do it as an embryo, rather than inventing it through a process of mutation and then natural selection, very severe selection to produce these conversion evolution. That's the standard model. It doesn't make any sense to me, but that is the standard model. Most oncologists, I should be a little more fair to them, they don't care about the origin of cancer, they're just trying to fix people. They're just trying to cure people. And I don't know anything about curing people, but we're trying to figure out what cancer is. They're very different processes, but you could argue that if you don't know what cancer is, how are you going to fix it? And that's what we argued here. So, this is 2011. Now, so basically, in this phylogenetic tree, the Adivism model says, "Okay, we got all these multicellular genes here, and then you are reverting to the older genes." So, cancer runs on these genes rather than these genes, suppresses disease. Now, that's a simplistic view, but that's what we're talking about here, a simplistic view of what's going on, but it's definitely a pattern that is recognizable among the noise. Just the arrow there. What you were saying, my first impression was that the genes are present there in called cancer, as you make the transition between the unicellular and the multicellular. Those genes are not in the unicellular bacteria, aren't they? They are. Yes, yes, yes, yes. The oldest genes are shared by everybody. We have, I think, you know, it's hard to find exactly what a gene is, but something like 50 percent of our genes are shared all the way down here at the bottom. And then it goes down, you know, 51, 60, 70, you get up to here, 98. So, just that, it percentage increases. For example, everybody uses DNA. Everybody uses ribosomes, you know, ACGT, et cetera. Lots of, lots of common biochemistry all over the place, not just a gene ages. It's not just a function. There's a cancer, it's not just a function of whatever the gene mutation, if your life was, that caused unicellular life to become multicellular. Say that again? Given that cancer is often such that we tune this in the proliferation of cells and just growing out of control, it has nothing to do with that evolutionary transition between unicellular life and multicellular life. What has everything to do with that transition? It has everything to do with that transition. Why? Because before multicellularity, before this, these cells were single cells or colonial. When you're a single cell thing, you can proliferate all you want. There's no limonage at all. You're only resource limited to your replication. But once you become part of an organized multicellular thing, that organism to exist has to suppress that replicative ancestral, I guess, tendency. And the more fancy your multicellular organism is, you've got to figure out where to suppress it and where not to suppress it because there are parts of your body where you need that mitosis going on. Hair, gastrointestinal lining, toenails, skin. These are the places that are high mitotic regions and these are places where they haven't suppressed it, or whether it's well controlled, but when you need it, they turn it on. And that's, for example, wound healing. I cut myself here. The cells nearby have to say, you know what? I wasn't going to reproduce, but now that I'm getting the signaling from the wound in the inflammation, I go through this whole process of turning on cell duplication, and the cells say, okay, they make them, and then they stop. Cancer goes, no, no, no, and doesn't stop. And the reason it doesn't stop is because the stoppers have been damaged. Another part of this model is that you have a company and you have a founder. It's very important to the company. And then you hire people. And they've learned a lot. They've been there for 10 years. Then you hire a summer intern. And then there's a problem. Somebody says, you know what? We're running out of money. You fire the summer intern, the most recently added person who is least integrated into your company with the exception, if they're really, really good, and you need them, but you haven't protected them enough, so you got to protect them. So that's the kind of what laughed in first out model, because when there's a structure to your DNA, which can protect some parts of the DNA more than others. You know, it's not just a linear thing where it's equally exposed to UV or equally exposed to anything else. No, they're wrapped around histones. They're the DNA between the histones. All kinds of ways you can protect them. You have a question? I love this model. Isn't there sort of an odd prediction here, which is that we should sometimes get mutations that just drop us a little bit earlier in the multicellular history? What disease is it? Or the embryological history? Yeah, so what diseases is it when some of my lungfish genes get expressed a little more properly than they often? What are diseases that when you're lungfish? I mean, when the, you know, when these unicellular genes get turned on, I have cancer. Yeah, all right. Shouldn't we have a law of... All right, yeah. Now, what we're looking at here is a theory of cancer. This guy I mentioned earlier, Tomislav Domolozet. He wrote a paper saying that a lot of other diseases have this using older genes, not the new ones. I haven't been following that research, but he, there's a paper written by him about your question. All right, so I had... That's the only way I can answer that. Well, there's a whole list of them. He had old diseases, new diseases, which genes have been not working, which genes are turned on to in the immune system, for example, to fight them. Like I said, it's a... Tom... If you want to... This guy. Right here. He's a very good guy. I met him a couple of times at some workshops, and I was very impressed with how well he understood what was going on here, but I still would encourage him to use different ages here, rather than equal things. All right, so have a look at him and you'll find that. Yes? Do any other processes in the body use those ancient genes? Yeah, all the time. That's what that... It's for particularly... Do you know what you're doing? Yes, yes, yes, yes, yes. And particularly... So wound healing embryogenesis, you can think of metastasis. What does that mean? Invading another the basement of your epithelial cells? That's exactly what a placenta does to the uterine wall. So there's nothing that cancer can do that normal cells don't do during some part of ontogeny and development. And I should... Some part, I really mean 80 to 90 percent of that part is the first... Well, when you're before you're born. So embryogenesis, why keep on using the word embryogenesis? That just means, you know, fertilized egg and then grow, grow, grow, grow, grow, and then you're born. In that period, all kinds of these old things and that paper I showed you was an example from hemoglobin. But I suspect you could find that for almost any protein. But it's illegal to do that on humans, so you gotta do it in mice if you want to make progress on this. Okay, so what is an atavism? So here's a nipple, I got one of them here, and there's a supernumerary nipple here. There's a breastline that we, our ancestors used to have, and when something goes wrong, it's the suppression of the extra breast, out pops the one that was was getting ready to form, but then a gene said, "You know what? You only need two. We're gonna turn it off." If something goes wrong with that, turn it off gene, then out comes a supernumerary nipple. Mark Wohlberg has one, you know, the guy in Planet of the Apes. I'm not sure if he has one or two, but here's a tail. There's webbing between the toes. You may be aware that when you're a fetus, you have webbing between your fingers and then through apoptosis, they get sculpted away. So there's your body for make something and then destroys it. The reason it makes something is because that is historical inertia of your genome. You also have a tail. If you look at the fetus, the embryo of a blue whale, you will see back legs on it. As a matter of fact, if you go to the Natural History Museum, you will see bones associated with the formerly the pelvic girdle of about 35 million years ago when whales knew how to walk and they lost them, but they didn't lose. Now, that's called a vestige. That's not called nativism. That's a vestige. It's normal. So, to make that distinction, here are vestigial features. This is this bone that you will see if you go to the Natural History Museum. Maybe the appendix is a vestige. Maybe wisdom teeth are a vestige. These things, this innicitating membrane, you'll see. You ever see a crocodile bling its eye goes like that? We have a vestige of that. Remember, we used to have a common ancestor with crocodiles and we still have a vestige and it's right there. It's that membrane just on the inside that looks like it would cover, but it's been atrophied. And also our tail. But these are normal things. Those are vestiges of things our ancestors had. They've just been wasted away, but they appear normally. Adivisms do not appear normally. They are when something has gone wrong with the genes that would have normally suppressed the production of that nipple or tail or webbing. Here's a dolphin. It's got back legs. Normal dolphins do not have them. That's an adivism. This is an adolphin. That's not an adivism. That's a vestige. It's a vestigeal feature. Is that clear? Okay. So, here you have, oh, here's that hind leg of a whale embryo right there growing. And here's that adivistic, normal, adivistic hind fin on a dolphin. Any case, here you have a fertilized egg and then you have a cellular cascade. You're differentiating yourself, differentiating yourself, differentiating. And then you would, if you have a suppressor, a leg suppressor, that's absent in tetrapods, and then in a normal dolphin, you do not have a leg. But if something goes wrong with that leg suppressor, then it starts to form this hind leg, or in this case, a hind fin. That's when something goes wrong. That's what's where it's an adivism. It's damage. And here, those are the stijol pelvic girdle in another citation. So, all your body is covered with cell differentiation cascades, because, you know, you could say, oh, I don't know how many cell types are there. There's 200 or 1,000. It's very undefined. But the point is that if there are, let's just say that there are 1,000 human cell types. If you go back a billion years, there were not 1,000. There were fewer. The cell differentiation cascades had not evolved that much into that many differences. And this is the type of thing you see in cancer that the cells are not mature. They de-differentiate, and so they're not specialized anymore. It's as if they only had access to a cascade which went so far a billion years ago, and not further. So, here, one cascade, he'm out of poetic. Right now, inside your femurs, your thing, your body is going through all this, reducing all these different cells, all these blood cells, for example. I'm not sure how many millions per hour or something, but it's a vast number. And when something goes wrong, just like in that whale, if something goes wrong with the gene here, then these will stay young and they won't mature into these things. And then you will have lymphoma or some type of overabundance of immature blood cells of various types. So, here is a guy, David Goode, and here's a student that he worked with, Anna Trigos, and over the past decade, they've written quite a few papers that have looked at aging the genes in cancer, as a function of Gleason scale, which is the scale of cancer progression that is used for prostate cancer. And so, what they found, and then here are the gene ages here, old genes are here, young genes are here, normal distribution in a prostate is here. Stage six, it's here, stage seven here. So, you can see there's a pretty significant decrease, or using older genes, older proteins in more advanced prostate cancer. Now, I'll show you this, but not that many, because oncologists are not convinced very much of this theory, they do not go to the trouble to make age as a function of grade. They just don't do it, because they don't agree that this is a legitimate model for the, what cancer is. Okay, what else? Okay, so we wrote this paper in 2020, cancer progression is a sequence of adivistic reversions. So, it's not just a new to old, but rather as damage accumulates, you're damaging the most recent layers, and then the next one, and then the next one, and the next one, and the next one. That's why I call it the sequential adivistic model. And that's what this looks like on this plot. Instead of just going, oh, these turn into these, you go boom, boom, boom, boom. And so, there should be some correlation as we showed in this data between stage and age. And there is. I'd like to see more data like that. I mean, this theory makes so many predictions that it's easy to invalidate, but in order to do that, you have to take it seriously enough to do that hard work. All right, so here's this thing again. So, here, this is 1 billion, 2 billion, 3 billion, 4 billion years ago, origin of life. Here's phylogeny. Here are all our ancestors. Here are our extant cousins' ancestors. And we used to be unicellular prokaryotes for the first 2 billion years, approximately. There was no oxygen in the atmosphere. We didn't have mitochondria. And that's what our ancestors were right here. And then oxygen came along. There was an endosymbiotic event in which a former free-living bacteria called alpha-proteobacteria that knew how to breathe oxygen and make the oxfas. That was incorporated into an amoeba. Then we had single-celled unicellular eukaryotes. And then those single-celled eukaryotes said, hey, maybe I'll have some friends. And so they started to form colonies. And then those colonies got a little bit more complicated. They got multicellular, but to get multicellular, remember, you had to turn off proliferation in most of your body to create a useful soma. You can imagine if your... Imagine if that didn't happen, when you were growing. You'd just get body would just get bigger and bigger and bigger. It would blow it out. As a matter of fact, my wife had what's called a peg. She was in the hospital, and she was being fed through a tube right here. They pulled the tube out. And what happened is the interior lining of the stomach started just growing undifferentiated cells. And so what they do, this common practice, they take silver nitrate, put it on it, and then it just all dies. It's not cancerous cells, but it is replication. And it's not controlled by guests because it's no longer inside the stomach. Those are my guesses. I'm hand-waving, but I didn't want you to know that. Okay, so what else? Now, 10 years later, Panahan and Weinberg came across and said, oh, you know what? There are more than just these six hallmarks that I mentioned. There are maybe 11. This is from this paper here in 2011. And on this, here's how they attack, here's how somatic mutation attacks these hallmarks. They said, oh, for tumor-promoting inflation, we do this. For activating inflation, when cancer does this, we do this. When we endogenesis, we do this. And so there's a whole series of targeting the abilities of cancer. And that's the exact opposite of the therapy that is recommended by our model. And I'll show you why. I call this the whack-a-mole. Most cancer therapy is anti-whack-a-mole. The reason for that is if you're targeting mitosis, mitosis and cell duplication is 4 billion years old. It's one of the oldest things you have. It is the most robust, most protected thing. It's the thing that cells love to do when they know a thousand different ways of doing it. And so if you'd use an anti-mitotic cell, boom, you just, oh, then it figures out another way to do it. You do this, you do that particular pathway, and then it figures out another way. That's because simply there's some cell plasticity, and it's one of the things that has been challenged for 4 billion years, and they've had to overcome all those challenges. So that's why I call most cancer therapy an anti-mitotic whack-a-mole. And I think that's holding up cancer progress. So what about adivistic therapy? I've just been talking for, I don't know, half an hour about this model. What does it imply for therapy? All right, so we wrote a paper in 2014 with a real oncologist, not two cosmologists, two astrobiologists, Mark Vincent in Ontario. And we wrote this paper, targeting cancer's weaknesses, not its strengths. So mitosis, we call cancer strengths. If that's the strength, what are its weaknesses? And the answer to that are the weaknesses are the things that cancer has lost the ability to do. It has learned and had de-repressed a lot of things that every cell knows how to do, but it has lost the ability to do the things that have most recently evolved. So, for example, here's now, here's a billion years ago, 2 billion years ago, 3 billion years. So these things, these are the earliest evolved capabilities. So this is like a number of capabilities. Lots of capabilities that are very, very old. Then they have stem eukaryotes. That just means, you know, like unicellular eukaryotes. And these are, well, well, these are metazoan, these are vertebrates, these are mammalian. So you can see that some things have evolved more recently, mammalian capabilities, if you want to call them. But others are vertebrate capabilities, etc. So the prediction is that cancer will lose the more recently evolved ones and maintain, robustly maintain these old ones. So let's take an example. You have an immune system. Now, simplistically, you can divide your immune system into an older innate system and a more recent adaptive system. The adaptive system is the basis for vaccination. You cannot vaccinate a bacteria because they do not have an adaptive immune system. They have an innate one. And that just simply means that the thing it fights viruses with are already in its genome. It doesn't, it's not adaptive like ours. It doesn't go through permutations to figure out, hey, what is it that's attacking me? Okay. Oh, that's what it is. Boom. That's adaptive. And so that's what we have. But it's recent. It's about four, five hundred million years old. How do we know that? By doing this phylogenous stratigraphy, looking at the genes involved in the adaptive immune system and figuring out how old they are. So we know that it's young. We know that that's old. Normal cells have both of them. According to this model, our relativistic model, cancer cells have this. That's simplistic because as you solve by those prostate cancer, it really, the damage has to be accumulate, cumulate, cumulate, cumulate. And you slowly lose the ability to do adaptive and you slowly lose these. And then it just goes that way. It's because the oldest ones are the most protected. All right. So here's a metaphor for what the adaptive therapy is. Again, it's attacking the weaknesses of cancer, not its strength. So imagine there are some cells. Here's a normal cell. It's got the fort with a moat on it. So there's the fort. Here's the moat. And the moat is something that has been involved recently. Now here's a cancer cell. It used to have a moat. But you know, some storm caved in the walls or they ran out of water. Anyway, the moat is no longer there. Why? Because it has been damaged by something. I don't know, tobacco. So this thing doesn't have a moat around it. It doesn't have a protective adaptive immunity. Normal cells have both. They have this protection and then they have this. So what the idea here would be you take a mouse and you, let's say you want to count, I don't know, pancreatic cancer. No, let's say liver cancer. You take a mouse and somehow it hopefully gets a mouse liver cancer, but it doesn't usually insert some human liver cancer. And then it has cancer. And it also has normal cells. It's a fortress with a moat, those normal cells. The cancer cells are just a fortress without a moat. So it also has an adaptive immune system. So you're going to develop a vaccine against some bacteria that you're going to attack this whole mouse with. But you're going to vaccinate the mouse against what you're going to do. So normal cells, which talk to the adaptive immune system, can protect themselves. And it's a big story about dosage. You can figure that out with the mice. And so you get the right dosage. You then vaccinate all your mice, the ones with cancer and ones without cancer. And then you give them this bacteria that's going to attack your liver. And the ones that are normal, mice, should do that fine because you've already tested that. The ones that have cancer, what happens there? The normal cells talk to the adaptive immune system. The cancer cells do not. The cancer cells can't talk to the adaptive immune system. They cannot be protected with the vaccination. So the idea is that those bacteria will then selectively find the cancer cells because of this adaptive, because normal cells have innate and adaptive. Cancer cells only have innate. You're taking advantage of the lack of an adaptive system. You're not attacking the cancer cells because they're expressing the innate system. That's what the whack-a-mole is doing. That's what somatic mutation theory is doing. And here's another example. Imagine Einstein. Okay, Einstein learned German, and then he came to the U.S. and he learned English. Right? So when he died, he was mumbling in German. He loosed, you know, your brain started to die and then you start speaking the language you grew up with, your native language, your mother tongue. So there's an example of if Einstein's a cell, in the early stages, he learned German, and then on top of that, more recently, he learned English. But then as he was dying, he lost the English and he kept the German. So that's kind of like a metaphor for what's going on here. And how would you attack, let's produce a whole bunch of Einstein's here, you got some Einstein's, some of whom are dying, they're cancer cells. Some of them have lost the ability to speak English, others speak English. They're normal, Einstein's, they can speak English, and German. What do you do to distinguish them? That's one of the biggest problems in cancer treatment is distinguishing normal from cancer cells. Well, what do you do is you give survival instructions in English. The only German speaking cancer cells will not understand that. They've lost the ability because it's a newly evolved ability, and the normal cells will understand it. You're not going around shooting people for speaking German. That's what normal cell therapy is. That's what normal SMT, somatic mutation theory therapy is. You're saying, what are you? Oh, you've lost English, you speaking German. Okay, we're going to kill everything in the body that speaks German. That's so stupid because normal cells speak English and German, not only German, not only English. So you're taking advantage of a loss. Another example. So here's a normal cell, I can do A and B. Cancer cells can only do something earlier A. And so what you have to do is you target cancer cells using what they cannot do, not what they can do. And that can do is exactly what I showed you, those hallmarks, how they were targeting cancer because of it, what it was doing. Not what, because of what it couldn't do. They hadn't identified what it couldn't do or they don't care. And so that's why this is important. It's almost the opposite of normal cancer therapy, and that's why I found it so difficult to talk to people who are married to the somatic mutation therapies because they say, oh, the cancer cells are proliferating. Okay, anti-mitotic. The cancer cells are doing this. Okay, we're going to combat that. It's just the opposite of what we're doing here. We're doing here is identifying what cancer cells cannot do and then putting them in environments where that disability kills you. That's kind of like the heart of the therapy associated with this atavistic model. I hope you appreciate how different that is from the normal somatic mutation theory motivated therapy that seems so simple, so straightforward. And we argue in this paper that it's the silliest thing to do. It doesn't make any sense at all because you're attacking cancer's strengths when you do that. And you can recognize that as a strength because you do it and then it figures out some other way to protect that ability. Why? Because this happened three billion years ago that this thing evolved or two billion or one billion. A long time has these cancer-like abilities that are unsurprised have evolved a long time ago and are well protected. So what else? Another metaphor you can think of is you make a whole bunch of, I don't know, Notre Dame's. And these are cells. And Notre Dame's all over everywhere, thought millions of them, trillions of them. And then every once in a while you get some damage. You know, maybe there's a fire. Paris. And maybe there's a bomb. Maybe there's an earthquake. Maybe it just gets old and there's some worms eating the wood. The point is that they will get damaged. And the first thing that gets damaged is the roof. The most recently added part of this building. And so the cancer cells, there's a normal, hey, that cathedral has a roof. That's a normal one. Over here it's lacking a roof. That's a, so what can not, what does the roof, what does this cancer cell without a roof, what does it do? Well, it makes it susceptible to rain or whatever else you want to put down on it. It would be silly to say, oh, those destroyed cathedrals, they have thick walls. They're doing something terrible with those thick walls. Let's shoot at the thick walls. That's stupid. What you need to do is take, find out, and identify what cancer cells cannot do. And the cathedrals do not have a roof, so use that. I think I got another. So, now, we talked about immunization adaptive and innate. And we talked about Einstein. But your body is made out of every system in your body. There are dozens and dozens of them which have evolved, whose genes we can assign an age to. And therefore, we can make predictions based on the theory. If you have cancer of what a particular organ, the genes that are regulating that organ and the cancer in its capabilities are older. And the newer ones are functioning in normal cells. So, you have a circulatory system, angiogenesis, tran, men's, rain protein. I'll give it, do I have time for one more example? Okay. So, another example is one of the terrible things about cancer is multi-drug resistance. You get chemotherapy and they say, okay, this is going to kill the cancer. And then the cancer figures out somehow how to get that toxin out of its system and survive. And one of the systems that does that is called, here, it's called ABC. This is called ATP binding cassettes. They are in your cell walls and they're the things that say, hey, there's some garbage stuck out of the cell. There's some more garbage stuck out of the cell. So, when you have garbage, we have toxic, you know, camber cell killing chemicals inside your, inside a cell, a normal cell will want to try to get rid of that. Interestingly, there are dozens and dozens of these molecules that do this. Some evolved recently. Some evolved a long time ago. So, here is the phylogenetic tree of these ABC transporters. Here is the shortest one, which is most like the original. It's the oldest one. Here is the longest one. It's mostly recently evolved. It has more changes between it and here. So, you identify, so you find out, okay, what are these new ones? These are, you know, there's a dozen new ones. What can they do? And they have, they've evolved for a reason. They're a little bit different from their neighbors because they can, I don't know, hold on to something with a phosphate or deal with smaller molecules. There's an n-parameter space which has selected this variety. The oldest one is the shortest one. Right there. Oh, that is ABCA5_1. That's what all of these are doing. They're just checking things out of cells. That's why they're called transporters. Anyway, so here's the longest one, ABCA6_2. That's the longest one and everything in between. Now, if you do a plot in this color plot, here are billions of years. Here are the ones that cancer uses and here are the ones that cancer has lost according to this phylogenetic tree. The ones in red are the ones that it preferentially loses ability of. The ones in blue are the ones it keeps. So, if this is approximately correct, you can identify these groups and figure out what they can and cannot do. What can the newly evolved ones do that are in normal cells that cancer no longer has access to and then you attack it with exactly stuff that the new things can handle but because the cancer cells do not have the new ones, they cannot handle it. That's a way to get a leverage into what type of drugs will or will not be successful when you're trying to kill cancer cells. That's another example. We're all talking about the same thing that is identify what cancer cells lose based on what was new and then leverage that question. They have nothing to do with phylogeny, gene agents, they have nothing. They don't even think about this. If there's multiple therapies that target different variants of this and this shows that some of them are more effective, then if somebody bothered to do this test, then they might be convinced a little bit. But they don't bother to do this test because they think the whole thing is I don't like that. I like SMT. It's kind of like I think one of the models that I guess David Deutsch would say explains everything, therefore nothing. That's the sad case of the understanding of most oncologists today and that's why they're so reluctant. I shouldn't say reluctant. There are quite a few people more theoretically oriented oncologists who are a little bit more open-minded because they don't have to save people every day. They can think a little bit and so they've read this and so they're aware of it, but they like a good scientist, they need more evidence. The good thing about this model is it makes all kinds of predictions everywhere unlike somatic mutation. I'll give you another example. You've heard of targeted immunotherapy. What do you do? You have this particular type of cancer. What does it have on the outside? This, this, and this. Then you say, "Okay, I'm going to train your T cells or whatever in my petri dish to identify that." It's kind of like you're acting as the thymus for these cells. Then you put them back in your body and then they attack the things that have cells that have those one, two, three things on the outside. Then, by the way, then it starts to be less effective. Why? Because the cancer cells are at least mildly plastic and if they're regressing, becoming less differentiated, they have then other things on the outside. Whatever those things are on the outside are part of the normal part of normal cells. We pretend that whatever cancer has on its outside is something, "Oh, that's unambiguously cancer. That's how I'm going to kill it." That's crazy because those proteins that are on the outside are normal proteins which are normally expressed on the outside during some part of development, according to our model. In somatic mutations, I say, "Oh, those are just there from mutations." Then what happens next? Well, let's say the cancer cells change the outside appearance and then they say, "Oh my gosh, it's trying to escape." It gives this agency to something that is just falling apart and defaulting to what every cell in the body already knows how to do. The same thing for cuddherence. You may have heard of cuddherence. Here's time to 100 million years, a billion years. Cancer goes through this progression of cuddherence. Cuddherence are the things that hold cells together. They're like any other system in your body. There are dozens and dozens of them. Each one of them has a certain time period where they evolved so they have slightly different strengths and weaknesses. The sequence based on the ages should go like this. The E's and the P's, the N's, the R's, the M's, the decimal columns, etc. These are the prediction, a very specific prediction from this model. Some people like Robert Weinberg at MIT have said, "Oh yes, cancer only goes from here to here." But that's a mystery. That's just somatic mutations happening rather than part of a predictive theory that the Adivistic model is. So to summarize, the Adivistic model predicts all kinds of wonderful things that have partially been substantiated. All the data we have that has tried to test it is consistent. SMT waves its hands and say, "Rutation and then cancer," without being as specific about the times, the ages of genes, phylogeny, or ontogeny for that matter. Adivistic model includes ontogeny because, as I showed with the hemoglobin model, when you were a baby, you did not use adult hemoglobin. You used older hemoglobin that had evolved earlier than the adult hemoglobin that you're currently using. That's what the sense of ontogeny recapitulates phylogeny means. Anything else? So, next steps. Well, I think we can do a lot better with final stratigraphy that I mentioned because we now know the ages and the times. Instead of 20 nodes, we have 37 nodes to use for times. The Adivistic predictions need to be tested. Particularly, cancer progression dependent transcriptomes. So most people are in the mindset, "Okay, here's a normal cell." And if you do that, you're not taking advantage of progression of that cancer. You're not sampling it as a function of time. Our model uses that data and says it makes specific predictions about what will happen as a function of time. Other models do not. Better differentiation cascades for normal tissues. So, we need to understand the cell differentiation cascades in a way that we don't yet. All over your body right now, some stem cells, pluripotent stem cells, no more tody potent stem cells. But you have pluripotent stem cells that are going to repair something. They're producing all those red blood cells that die. Your body is almost like a body. They're the little bodies inside of your body, which are the result of these cell differentiation cascades that go on. And when something goes wrong with them, then you produce immature cells. When I say immature, also older cells. That's why I say older because they're running on gene regulatory networks and genes that we can show are older than the ones that would have been running on. And that's it. Imagine there were investors in theory or philanthropists who wanted to actually do that last point of time. What would a type of type A, a large team of people would take two research graduate genes with some access to a single lab, ideally, or minimum viable project? Well, I thought a little bit about this, but not that much. I would say two postdocs and, I don't know, a million dollars or something to pay the postdocs and pay for the lab equipment that might be used at ANU. Another shortcut to that would be to find somebody who understands this and is sympathetic with it and, therefore, can test it, who's more of a traditional oncologist and has played with mouse models. I'm not a doctor, so I'm not having patients. Please, doctor, help me. I'm not that. But doctors are in that position. But as an abstract theorist who's talking about big ideas here, I would test it on mice first. But I'm sure the people who are the cancerists would give me the cure quickly. I don't know what the ethics of that are. I'm not a doctor, but I would suggest to test it. There's so many different tests that can be made using mice, and it's ethical to cut up a mouse when it's one day, old two days, old three days, old et cetera, to test whether these, first of all, the ontogeny, the old hemoglobin, for example, is being used and how that progresses. But also, you can keep the mice alive as cancer progresses, so you can keep track of cancer progression. You're not trying to interfere with it. So, you can see that progression and then see if this model is correct about you getting progressively older genes that are running the capabilities of cancer cells, and then you have, well, they use the therapies, right? So, the one therapy I told you about was the adaptive versus innate therapy thing with the, you know, get a vaccine for the mouse, try to get a liver, get some bacteria that's going to eat, kill liver cells if they do not, aren't protected by the adaptive immunity, and then let that protection, the relative protection of cancer cells versus normal cells, be the solution, where you're taking advantage of what cancer cells cannot do, not targeting what they do do, because what they do do, any normal cell sometimes does that. That's why when you get cancer therapy, your hair falls out. Why is that? Because your hair normally goes through mitosis to produce those hairs. Same thing with your gastrointestinal lining. You have all kinds of, that has to, you have digestive juices there that's not only getting the meat, it's also digesting yourself. So, you've got to replenish that all the time. So, you have mitosis going on all the time. You give somebody anti-mitotic drugs. What does that do? It beats the shit out of their interior lining there, and so they feel terrible for, you know, what lots of side effects with anti-mitotic. Why? Because you're attacking the strength of cancer. It's been around for three billion years. It's not something that has recently evolved, and those are the things cancer cannot do. That's what you need to take advantage of. Yes. So, the two types that you mentioned, the adaptive immune system goes away, and then some of those [inaudible] Well, let's not, let's not take that. I've said that several times, but it's important not to take that so seriously, because it's a really complicated thing, and the damage that is setting that off is stochastic. You don't just say, "Oh, I'm going to damage that," that turns it off. It's not like that, but there you go. Yeah, all I was going to ask was, if you had the opportunity to, what pathways would you try to study next, besides the ABC transverse image and adaptive immune system, like anything else that might disappear? The whole thing, the whole thing, every single system in your body is the result of a hierarchy of evolution, and you can identify, since we now know the ages of the genes, and, well, the next step, I think, is figuring out not just the ages of the genes, the ages of the regulatory networks, because what happens, you're not just switching from, to switch from using one gene to another, you have to have, there are a whole bunch of genes that have to talk to each other to do the next capability. It's not just one gene, "Okay, now I can talk French or something." You have to have this, and this, and this, and this, and then progression goes on, this gets damaged, and then it reverts to the earlier one. And so, so the gene ages that are involved in those gene networks get older, but also, in some sense, the gene regulatory networks are getting older. That's the Warburg effect, for example. So, there you have, everybody does oxfos, you got the ATP, and then what happens, oh, that kind of gets damaged. And so, what happens, you revert to glycolysis. That's what we did for two billion years before we got the mitochondria. So, you're reverting to something not evolving a new ability, what? >> Yeah, no, I'm just going away. >> Okay, good. >> That was my question. What about targeting that? >> If the cancer cells have loss, the ability to drive energy from the lung is going to take. >> Right, so, one person says, "Okay, it's using a lot of glucose. Let's take glucose away." But remember, glucose is being used all the time by the new stuff and the old stuff. Oxfos uses glucose. It just does it a different way. So, how do you target that particular metabolic pathway, for example, right? Let's push it. Let's see, so cancers are losing the ability to do oxfos. One way might be to try to over oxygenate the environments of these cells because that kind of pushes them a little bit more towards oxfos, which the cancer cells cannot do, and therefore, they don't like it as much. That would be one way. But maybe you can think of another. The poll point is we know what it does and how it's reverting. How can you take advantage of that lack of ability in oxfos to then target cancer cells, not targeting glycolysis because that's part of what normal cells can do, and there's oxfos here. Targeting the absence of oxfos is what's important. Yeah? >> So, there is the correlation between the spatial cancer and the age of the genes. There seems to be. Yes? So, it's not the mutations that are recent. When you have a genome wrapped up in all kinds of ways, and those wrappings determine which are the genes, which areas of the DNA are more exposed to UV or chemicals or maybe tobacco smoke or something. So, there is a wide difference between how much your body polices or protects this part of the genome versus this part of the genome. So, what this model involves is, you know what, the new guys, we've got one policeman who are watching 10 people. Over here, we've got 10 policemen watching 10 people. Over here, we've got a giant police force making sure that nothing interferes with these robust things. If that's, you know, vaguely correct, then when something happens, UV, chemistry, carcinogens, then these guys are the ones that are less protected. Therefore, they will be damaged, and whatever regulatory networks depend on this will fall apart and be damaged. Slowly, and then it will revert to the older ones that have not been as damaged. There is not like a built-in rewind function in the cell that reacts to them by rewinding into. There's partial ones, but they go away, the more cancer progresses. So, it can go kind of like they figure out a way to go, but the overall progression is in the direction of total different, non-differentiated cells using old genes and gene regulatory networks. >> So, can we get back to what you want to do with this one? >> Which one? >> Next one, after that. >> Uh-huh? >> So, it's just like a simplified whole profile. >> That's what I just did for an hour. >> [LAUGH] >> [INAUDIBLE] >> [LAUGH] >> [INAUDIBLE] >> You've got the two different aspects of that, and you've got to, I'm assuming that it's tough to gene that they shade through from normal. You're talking- >> [INAUDIBLE] >> Here, here, yes. So, this is age, right, and these are the branch lengths from the root. So, how far from here it is, and- >> [INAUDIBLE] >> Healthy cells have all of these. Cancer will have these being more easily damaged. Why? Because they're the longest ones more recently evolved. >> [INAUDIBLE] >> This section here. >> [INAUDIBLE] >> A healthy cell would use all of these. >> [INAUDIBLE] >> Yes. >> [INAUDIBLE] >> Well, yeah, but this is not metatabolism, these are ABC proteins, right? These are, these are transporter getting, this is, a diagram is in the context of getting rid of drugs from a cell and all the different ways. It has- >> [INAUDIBLE] >> No, there's no energy here. What's here is how good you're collecting garbage from inside your cell, the drugs that you've been exposed to as a cancer cell, because somebody's trying to kill you. >> [INAUDIBLE] >> Well, they're all correlated in ways that I do not know about, if that's your question. >> [INAUDIBLE] >> Yeah, yeah. Well, this pattern is the same in every system you want to think of. I just don't know the correlations between the patterns. Whether, for example, when you have, when you are up here, when you have reverted to these ABCs, you necessarily have reverted to, you don't equally get each cancer hallmark in every single cell. It's not an equal distribution kind of thing. Some cancer cells in different parts of your body would have this particular hallmark. Others have those in these two. If I were an oncologist, I could tell you how that relates to each other, but I'm not. >> [INAUDIBLE] >> But can I interrupt you? What's really good is read the paper, and you can see the red, and the bold, and the not bold. Those are the ones that have been identified in cancer cells, themselves. And so, partially this has already been looked at. >> But go ahead. >> Yeah, so, for instance, the metabolic theory professor, which in energy system a cancer is from mitochondria, amino, or jusac, so it's what you're talking about here, is the expression of the whole genes in the cell. Because the whole energy system itself, for instance, actually, is available in the accident. >> Well, that's what this is here. >> Yes, so, in fact, what you're saying is the whole genes are representative of the switch into glycolysis, which is- >> An overexpression of the old genes in cancer cells is an expression of cancer. >> So, I think- >> And the loss of the oxfos here. This is new oxfos aerobic respiration. That's new. It's in red. It fails first. It starts to fail. Then we have these guys here, and then we have these of the most protected ones here. Maybe even there's a sulfur metabolism three billion years ago, very, very early on. We don't know. That's why there's a question mark. >> Yeah, so, most cancers revert to glycolysis, which is the old expression of the genes, because it's an old pathway, energy pathway. The question is, are the genes driving that switch? >> Well, this is the one part where the somatic mutation model and the zitavistic model overlap, in the sense that we think it is gene damage and damage to genes that are producing this reversion. In the somatic mutation theory, it produces anything and then gets selected. In our theory, it damages, and then it reverts. I guess in your theory, it's the warberg effect, which then cascades into other things. Is that right? >> My question would be, well, two gene hot question really. Is it those cancers that have been found don't have driving mutation? So, how would that probably explain why the other thing would be, as a C of reason, say, metabolic theory isn't my thing. I'm sure my life, but the metabolic theory in C-free would say that the oxygen becomes damaged or mitochondria becomes damaged. That forces the change. Because that change occurs, then you see downstream or regulation of the gene. So, what causes the switching energy in this? I know that in your model, it's a switching energy that comes first, and in this model, that's not the case. In this model, it's the damage that comes first of an arbitrarily large subset of different cell types, much like the somatic mutation theory. Take it? The new genes that are involved in every single one of these if feels the illogical issues. Well, when you take driving mutations, so in any process, there is being regulated. So, cell proliferation, for example. This is a cell cycle. Matter of fact, here's a very important thing. If you look, if you Wikipedia cell cycle, evolution and cell cycle, you will see what is the mammalian or vertebrate cell cycle. But to make progress on this model, you need to know the bells and whistles as a function of time that have been added to the cell cycle. And the cell cycle of a bacteria, or let's say a prime emissium, is different than ours. But no one is going to the trouble of figuring out the exact differences along those ancestral. Remember that ancestral? You can say, "Okay, what was this one doing? What was this one doing? What was this one doing?" And then you get an estimate of when this stop point was made, when this checkpoint was made, when this checkpoint. And so, that's the prediction then, as cancer progresses, of which checkpoints are going to be removed to allow this to turn. And then it advances, and it turns even more. And so, it makes a very specific prediction about this particular, this is cell proliferation. So, unlike the somatic mutation model, we said nothing about this, nothing with age. But I think, see, your model is very different from this model because you have an initial cause of cancer in your model is... What? Okay, fungal pattern is okay. Right. And this has nothing to do with fungal pattern. But it does have to do with damage, right? To the extent that your model depends on damaging to different genes, that's overlap. The same thing with somatic mutation theory, it's overlap to that way. Well, I think we all agree that something is being damaged. And in our model here, and in the somatic mutation model, it is the genes, gene regulatory networks that are being damaged by all kinds of things, viruses and carcinogens, tobacco, even obesity. And age. And age. So, I guess, the one bottom line you can say is that if this is correct, we can do a lot to figure out what cancer is and to... I wouldn't say cure it, but I would say manage it in a way much better than has been done today. And I think, I don't know, like one third of the people in this room were going to die of cancer. So, if you'd like five or ten more years of life, is it one and two? Oh gosh. Anyway, it's a big problem for longevity. And this is, I think, part of the solution. I don't think it's going to keep people living forever. I don't necessarily think that's a great idea. But enlarging the health span is something that I think we'd all appreciate. If you'd like to contribute to top cast and our ongoing endeavor here to instill a little enthusiasm into the world for unbounded progress and more rapid error correction, contribute at my website, at www.brethaul.org right here and follow through to the donate buttons or to the Patreon links. Until next time, stay optimistic and have fun!
