Transcript Disclaimer – Please note that the following transcript has been machine generated by an AI software and therefore may include errors or omissions.

Robin Daly
Hello and welcome to another Yes To Life show. I’m Robin Daly, hosting the show for you, and I’m also the founder of Yes To Life, the UK’s integrative cancer care charity. On last week’s show, I introduced you to Mark Lintern, someone who’s had cancer himself in his late twenties, but who’s gone on to spend over eight years researching cancer in order to try and find out what is actually causing it and what its mechanism is. This has been more than a labour of love as perhaps you can imagine, but Mark has been rewarded with some groundbreaking discoveries that are more than worthy of serious consideration. If you missed last week’s episode, then I suggest you listen to that before this episode. Just go to yestolife.org.uk, click on the link to the radio show page from the home page, and there you can find a link to last week’s show, or indeed any of the other last four hundred or so shows. So now, I’m going to pick up with Mark from where we left off at the end of last week’s show. Hi again Mark, welcome back for part two of Cancer Through Another Lens.

Mark Lintern
Hi again, Robin, thank you for having me.

Robin Daly
Yeah so I’m looking forward very much to today’s episode. We’re going to get stuck into the cancer science and start to find out some of the detail of the journey of discovery you’ve been on these last eight years. For any listeners who are a bit wary of cancer science and are wondering if they’re going to be able to keep up, fear not. Remember I’m not a cancer geek myself although I do know where to find quite a few if I need one. So I’ll be aiming personally to keep everything as straightforward and graspable as possible. So at the end of the first episode you finished by introducing us to the 10 hallmarks or distinctive behaviours of cancer that have gained very wide acceptance within the scientific community. There was a reason that you wanted to describe these hallmarks to us that’s related to your journey and the point at which they provided a new focus for your work. Do you want to pick the story up from there?

Mark Lintern
Yeah, so it’s quite interesting when you’re researching something as complex as this that you need something, you need a foundation from which to kind of bounce ideas from to study the disease. And I came across the Hallmark list, I think I mentioned a little earlier, when I contacted Thomas Seifried. So he advised that to better explain cancer if you can with any particular model that you’re presenting, it would be preferable to understand or evaluate each of the Hallmarks that currently exist. So do you want me to go through each of the Hallmarks very quickly?

Robin Daly
I think briefly it would be quite interesting just to know at least what they are, yeah.

Mark Lintern
So, for cancer to be classified as a cancer, it would need to express pretty much the 10 key hallmarks that Han Han and Weinberg proposed. So, these are accepted conditions associated with the disease. So, uncontrolled growth would be the first one, growth signal failure would be the second one. So, the cells, cancerous cells essentially do not have control over how they grow, they just grow out of control. The third one will be cell death failure. So, these three essentially lead to the development of a tumor because the cell should, it has the mechanism to commit programmed cell death and this usually happens when the cell is damaged beyond repair or where the cell will be detrimental to the host if it continues in the format it does. So, programmed cell death is there to protect the host from damaged cells. When this fails obviously we have the development of a tumor especially if there is an uncontrolled growth occurring as well.

Robin Daly
Right okay so just to be clear so that’s a natural mechanism that kind of does a housekeeping, clears up any cells that are in bad condition and says okay these are not doing the body any good so they commit what is called apoptosis or programmed cell death and off they go and they’re excreted from the body so that that mechanism is a bust in cancer or is not working anyway.

Mark Lintern
Yes, essentially. Cancer cells appear to be a lot harder to kill than healthy cells, they resist cell death, essentially. And then we have Hallmark IV, which is that abnormally, cancer cells have limitless growth. Not only are they growing out of control, but they appear to be able to grow limitlessly. And then we have Hallmark V, which is essentially angiogenesis or blood vessel growth. So the cancer cell requires extra nutrients in order to continue its sustained growth pattern. So the rapid growth that these tumors tend to have means that they outgrow their blood supply. So at some point, they need to regrow that blood supply to supply them with the extra nutrients they need to continue to grow. So then Hallmark VI is related to the spread of the disease to other areas of the body, which naturally occurs after a period of time and is the most deadliest aspect of the disease. This is known as metastasis. Then Hallmark VII, which we’ll refer to quite often, is, reflects the abnormal energy or abnormal metabolism of the cell. So the energy system of a cancer cell operates, appears to operate very differently from that of a healthy cell in that it relies quite heavily on glycolysis and various other energy pathways, as opposed to the path that healthy cells would use, which would be oxidative phosphorylation, or energy being created by oxygen through the mechanism of mitochondria. We can go into more detail on that a little bit later. So Hallmark VII reflects the abnormal transition in the use of energy. Hallmark VIII refers to immune evasion. So the idea obviously here is that even if cancer cells start to develop, the immune system should technically destroy them before they become an issue. However, this doesn’t appear to be the case and the immune system seems to fail at certain points, which allows the tumor then to develop.

Robin Daly
So that’s another natural housekeeping mechanism that we got to get rid of anything that shouldn’t really be there and but again in this case it’s not really working so that because these cells seem to be evading that system they go under the radar so to speak.

Mark Lintern
Yes, so these are all hallmarks that need to be explained and the reason for these issues occurring. There are two more, Hallmark 9, where it reflects the damage to the cell, essentially, the DNA damage that occurs, and Hallmark 10 reflects the inflammation that occurs, because we see that inflammation appears to be a precursor of oral cancers, or chronic inflammation.

Robin Daly
Okay, so it’s there in every case, basically. That’s where it’s a hallmark, yeah? Yeah. Yeah. Okay, great. So that’s what we’ve got. And you’re saying that Professor Seifried, who you contacted, advised you to use these as a benchmark, if you like, to measure up any ideas you might have about what cancer is, how it’s working against these hallmarks to see what can it explain these behaviours of cancer. Yeah.

Mark Lintern
essentially, we need a foundation on which to explain any particular theory so that we can marry each theory off against another. And Hannahann and Weinberg provided us with at least 10 of these foundational hallmarks that all cancers share. So this enables us to assess each theory upon these particular traits of the disease. Without this, it’s very difficult to assess one theory from another. There are several other aspects to the disease. These 10 hallmarks are just a beginning, essentially an initial step in this process of trying to understand the disease. There are many more aspects to it, but they basically help us to identify particular aspects of the disease that need to be explained. So it’s good to have this foundation.

Robin Daly
Yeah, fair enough. Okay, so they did this. They’ve actually been around a little while, haven’t they, the hallmarks. They’ve been growing in number, but I think the first hallmarks came out just after the turn of the century, but we got to 10 and there are kind of four more in the wings at the moment, which are under adoption maybe.

Mark Lintern
Yes, so they’ve been updated since, so like you say, there were six initially. And then as research has progressed, another four have been added. And then since then, very recently, I think, earlier on in 2022, Hanahan proposed another four based on more research that has occurred. It’s a development of ideas and understanding.

Robin Daly
Okay so all right so this is your measurement tool then you went away with to start measuring anything you’d found how does it how well can it explain these 10 hallmarks. So out of interest obviously you’ve done quite a bit of research into the mainstream thinking about cancer the somatic mutation theory and you already started looking a bit outside the box by the point by that point but nonetheless you must immediately have thought to yourself okay so how does the mainstream theory actually stack up against these hallmarks how well can this theory explain the behaviors of cancer so what did you find out there?

Mark Lintern
Yes, so that was very interesting because when I was looking for each particular aspect of the disease to be explained, it was almost a sporadic explanation in the sense that, so for instance, the p53 gene is classed as the cell death gene effectively that deals with cell death in the cancer cell through the somatic mutation theory. However, when we look at the evidence, I was assuming that the gene would be suppressed or mutated in 100% of cancers in order to explain that cell death mechanism. So you would expect to see all cancers showing a mutation in the p53 gene, which would suggest that cell death could not occur. However, that doesn’t appear to be the case. From the cancer genome atlas data, it seems as though only up to around 35 or 40% of cancers have a p53 gene mutation. Now there are other, obviously, other DNA genes that can instigate apoptosis, but again, there doesn’t seem to be a correlation that can explain the cell death failure mechanism using the somatic mutation theory and DNA genes. What I found was there was a lot of randomness associated with the somatic mutation theory and the mutation of DNA genes, even to the extent that in some cancers, there were no driver gene mutations that appear to be driving the disease. So essentially, in some cancers, none of the hallmarks were explained.

Mark Lintern
So there’s this issue where I was expecting to see a pattern, and I think as the DNA theory was originally presented, or the somatic mutation theory was originally presented, was that a pattern of specific and sequential DNA mutations would be revealed essentially when we had the data from the genome APIS project, which was in a sequencing project to try and discover which mutations occurred in cancer cells. But that didn’t transpire. What transpired was that the mutations appear to be random, not only from one cancer to another and one tumor to another, but from within the same tumor. So it became difficult to discover the actual specifics of the mutations that could actually explain each stage of the disease or each hallmark of the disease, and that for me threw a red flag.

Robin Daly
Right. Interesting. So, yeah, they went off expecting to find that, yeah, there’d be these nice patterns in there. They’d see, okay, all the people have this type of cancer. There’s this pattern of gene damage here. So we know what we’re working with. This is the foundation of the thing. This is what’s driving it along. And this suppressed gene here creates this effect, this hallmark, and this one drives this hallmark. It’s all going to be nice and simple and clear, like a map. But as you say, it hasn’t turned out that way. And it’s very interesting for you to say that actually there are some cancers that don’t have any at all, any damaged genes at all. And therefore it’s difficult to say, well, as you pointed out, first of all, you can’t explain any of the hallmarks using genetic theory when there aren’t any mutations. But also it kind of undermines the whole concept that that could be the beginnings, the actual foundation of the disease. There’s just not enough there to pin your hopes on, really. So that must have kind of focused your attention elsewhere. I can imagine you said at that point when you found that out, okay, I’m not looking for any more answers there. Would that be right?

Mark Lintern
Absolutely. The more I tried to do the research on this and dig deeper, the more it became apparent that the somatic mutation theorem was having difficulty explaining these hallmarks. So I came to the conclusion, being as though I’m a non-scientist, I obviously can’t do any lab work.

Mark Lintern
move this forward from a DNA theory or somatic mutation theory perspective. So I realised there was probably one of two scenarios that has come out of this information. It could be that, quite simply, that cancer is just extremely complex. It could be a DNA mutation disease. However, we just don’t have the technology at the moment to unpick the puzzle, so to speak. So in that respect then, it’s up to the brilliant minds of scientists and new technology possibly to uncover the details of these combinations of DNA mutations. So that could be one reason why we still have an issue. It’s just simply too complex at the moment to understand.

Robin Daly
Right, so you’re saying that there’s not a direct relationship like you described a minute ago about like you look for a problem in the p53 gene and therefore you know this is what’s driving this hallmark, yeah? Yeah. So it’s not as simple as that, it’s much more complicated than we’ve yet to work out the the answers. Yeah, so one more.

Mark Lintern
One could argue that somatic mutation theory could be correct, it’s just far too complex at the moment for our current technology to understand the detail of the disease. That’s one perspective. But then there is another perspective, which is that quite simply, DNA mutations are not driving the disease, which would explain why we cannot explain the hallmarks at the moment. And that’s a process that I went down because that’s the only process really I could take at this point in time. So I started evaluating that side of things. And that’s where I realized that there were other theories of cancer.

Robin Daly
Right, so these are other people who think that maybe it’s not Gene’s doing all the action and there are other things at work. So yeah, really interesting. Give us a little bit of a tour. What else is out there?

Mark Lintern
Okay, so we have, I suppose the main theory is the metabolic theory, which deals with essentially Hallmark seven, which is abnormal metabolism in cancer cells. Then we have other theories such as the stem cell theory, which seems to focus quite heavily on the limitless growth of cells because stem cells are have this ability to essentially create a limited number of cells. We also then have the atavistic theory, which tends to deal with tends to try and explain cancer in the sense of an activism, an old metabolic programming system that the cell is reverting to because of particular damage to the cells. So it’s almost giving the cancer a personality in the sense that damage is happening and it’s reverting back to an old evolutionary form of energy in order to survive as if it’s a new species, essentially. We also have the tissue essentially reduces the ability of that tissue to provide certain suppression or suppressive signals to the cells that would normally be in place. And that allows for excessive growth of tissue forming a tumor. We also have particular theories associated with viruses and bacteria. There are many more besides, but generally they look at the cells, they look at cancer in a way which is reminiscent of damage occurs to the cell leading to some sort of malfunction in the cell and then that leads to cancer.

Robin Daly
Okay, so I imagine you went out with your new barometer of the hallmarks and you started measuring up these different theories. So is there kind of an outright winner amongst them?

Mark Lintern
Well, yes, the metabolic theory appears to be far superior to most of them, given that it appears to be able to explain a vast majority of the actual hallmarks. The detailed research that I did, I was looking at all different aspects of disease, so I was looking at all different theories to try and explain these hallmarks. And there are many, several other theories can explain several different hallmarks, obviously. And I wouldn’t say that any one particular theory is, you know, absolutely correct. It’s this one particular mechanism pushed by a particular theory. They all seem to merge between each of them. That’s what I found. And my perspective at that point was, well, we have all these different theories. They seem to be just competing over which part of the cell they believe to be the underlying mechanism, where there appears to be many different aspects overlapping. Certainly, there was one particular theory being metabolic theory that seemed to account for a lot more than the rest.

Robin Daly
So what you’re saying is that in general they lean towards being able to explain a different group of hallmarks to another one. Maybe they were strong on some hallmarks, weaker on others, but out of them all the metabolic theory can explain more of the hallmarks in total.

Mark Lintern
Yes. And what I found was, as I was going through the Hallmark list, there appears to be certain Hallmarks that, or a particular Hallmark, which is more dominant, you could say, which would be Hallmark 7, so 40 energy system, because the nice thing about the metabolic theory is it’s recognized one of the Hallmarks, that abnormal metabolism is a key feature of all cancers. So, as with the somatic mutation theory, the issue I found was that there didn’t appear to be much consistency, and that consistency wasn’t able to explain the Hallmark. So, we’re seeing random DNA damage occurring, and it was that randomness that that prevents us from explaining the consistency of the disease, which I refer to as the Hallmarks that occur in each case. Whereas the metabolic theory has identified a consistent factor that is involved in pretty much all cancers, which is this abnormal metabolism that occurs.

Robin Daly
That’s interesting.

Mark Lintern
And this is one of the crux of really the research that was performing I, I found it difficult to ascertain that randomness could cause the consistency of the disease and there was this conflict between this, this notion of randomness causing consistency and the need to explain the consistency of cancer. Yeah, absolutely, because random. Yeah, randomness can’t really generate the consistency and so the first part of the consistent puzzle and I fell upon was the fact that most cancers develop a faulty energy system or abnormal energy metabolism.

Robin Daly
OK, so that’s kind of right at the heart of the metabolic theory. So, just in numbers terms, what score do you give the somatic mutation theory in terms of its ability to explain hallmarks and what does the metabolic theory give?

Mark Lintern
Okay, well, I could only find that two of the hallmarks out of the 10 DNA damaged information could be explained by the somatic mutation theory. But even then, that’s not explained through the mutation of DNA because carcinogens can explain the random DNA damage that occurs and the inflammation that occurs also.

Robin Daly
Right. So the cancer causing substance itself or energy, whatever it is, you know, smoke or something could be can actually explain those two hallmarks without the need for DNA damage. Yes.

Mark Lintern
So I just found it very difficult to pin down a consistent pattern of DNA mutations that could explain the rest of the hallmarks.

Robin Daly
Okay, so it’s two at best. Okay, so how does the metabolic theory shape up?

Mark Lintern
I mean, obviously, this is my assessment that scientists will contend this assessment. But from initial, the initial look at the metabolic theory is that it can explain nearly all of them. However, after doing a detailed assessment, there is contention over Hallmark three cell death failure, the faulty energy system, Hallmark seven or abnormal metabolism itself, while abnormal metabolism occurs, there is contention over whether the metabolic theory has identified the underlying mechanism responsible for that abnormal metabolism. Also, immune evasion appears to be in contention.

Robin Daly
But at least at least seven they’re home and dry with. At least seven. Yeah, so a very different picture. So it’s clearly, you know, got a lot going for it in terms of it’s the model that’s being used must be close in some way to the actuality for them to be able to explain so much of the behaviors of the disease.

Mark Lintern
Absolutely. It also appears that the abnormal metabolism is a key aspect of cancer. So the rest of the hallmarks or most of the rest of the hallmarks appear to be a downstream event from that as a result of abnormal metabolism.

Robin Daly
right so okay it’s called the metabolic theory that’s very good so they’re placing a lot of emphasis on on metabolism and as you say this is hallmark seven so i just want to go into this particular hallmark a bit more because it’s obviously uh an important player in the journey here um and you know it’s it all goes back to the guy who uh the effect of hallmark seven is named after mr alto warburg uh do you want to tell us a bit uh about what warburg found exactly uh what the warburg effect is and uh really place that if you like in perspective in the in the uh scientific discoveries around cancer how that discovery sits and we’re talking about 100 years ago now

Mark Lintern
Yeah, I think it’s around the 1920s. Yeah. Professor Warburg, I think he’s pronounced Vollberg. Probably is, yeah. We’ll continue with Warburg. Yeah, so he discovered that cancer cells appear to ferment glucose. So rather than using oxidative phosphorylation, the use of oxygen to generate ATP energy for the cell to operate through mitochondrial oxfoss pathway, essentially, they seem to switch their energy to what you could say is the backup energy system of glycolysis within the cell. So this occurred, he noticed in the presence of oxygen. So this indicated to Otto Warburg that mitochondria, which would normally produce the bulk of energy using oxygen, were faulty in some way, which led to the notion that mitochondria are damaged. And therefore, that is essentially driving the energy switch or the metabolic switch to glycolysis or aerobic fermentation, as I think he termed it.

Robin Daly
Right okay so I just want to go back over that a little bit then. So you use the term backup system so the thing about glycolysis is it is not anything unusual in and of itself is it?

Mark Lintern
No, it forms part of our natural energy metabolism. So essentially, there are several different mechanisms. It’s a lot more complicated than I’m explaining here. But the way I explain it to the public or lay people is that there are essentially two energy systems and they work in conjunction with each other. So sometimes when we exercise, we need more energy than is required or can be produced via the oxygen-based energy system, let’s call it, through mitochondria. So say, for instance, when we sprint, we tend to require energy very quickly and the glycolytic energy system, which I refer to as the backup energy system, can provide that energy, but that’s through a process of fermentation of glucose without using oxygen, which results in the production of lactic acid. Now, this enables us to generate energy quite quickly. However, it can’t be relied upon because it’s quite corrosive and uses quite a lot of glucose in the process. So it’s there as a backup to help us in this fight or flight mode. When we sprint, try and get away from danger, essentially.

Robin Daly
Right, it’s a very useful thing and we all have direct experience of the process you’ve just described, I mean as much as the lactic acid production, you said is very corrosive, you can actually feel it.

Mark Lintern
Yes, so obviously if you sprint or you do anything quite quickly with your muscles in the sense that you can expand your your fist and contract it very quickly in a short period of time, you’ll find it difficult and that will be the buildup of lactic acid in your muscles, which essentially reduces the efficiency of your muscle at that point, so it can’t be sustained for too long.

Robin Daly
Right. OK, so it’s important to know that it’s a normal process. I think that’s very important to underline. But what Wahlberg identified was something particular to cancer cells that was abnormal. And it wasn’t that they used that system. They used that system when they didn’t have to.

Mark Lintern
Yeah, so when oxygen is available, mitochondria should technically utilize oxygen for the process of energy. However, in spite of there being oxygen or sufficient oxygen present, cancer cells appear to prefer the backup energy system of glycolysis instead, which indicates, which indicated at least to to Warburg, that mitochondria are 40 and that maybe this was the underlying consistent mechanism of the disease that was driving tumor growth and all the rest of the hallmarks.

Robin Daly
Right. Well, and a very sensible conclusion. That’s certainly the way it looked, isn’t it? Okay, the normal energy system is not working. It’s broken. You know, why isn’t it turning back to using oxygen when it can? It must be bust.

Mark Lintern
So, and the interesting thing is that the glycolytic energy system is a proliferative energy state. So that would explain why, to a large degree, we have uncontrolled growth and possibly the growth of the tumor, because the cell appears to be stuck in this proliferative glycolytic energy metabolic state. So I can see why, you know, proponents of the metabolic theory are pushing this.

Robin Daly
Yeah it does make sense. So there he was a hundred years ago he came to quite a reasonable conclusion at that point about what was wrong with cancer and whereas he got recognised for his discovery somewhere around that time certainly not long afterwards over the years it didn’t seem to really change the course of cancer sounds so much it was just like oh yeah he’s recognised something that happens and it wasn’t given significance in the way that he thought it had. I remember reading that how frustrated he got he lived into the 1970s I think and he was totally frustrated by the constant fascination with finding things that cause cancer the kind of daily male effect if you like this causes cancer that causes cancer too much of this cause you know and finding endless carcinogens he said was a total distraction from the one key thing that he discovered back in the 1920s so that was interesting he sort of stayed true to that if you like all the way through and the thing was though that the conclusion he’d come to which was reasonable given the science he had at the time given the technology which unveiled really that the genetic theory has got some holes in it by actually getting the genome out and shaking it around and seeing what’s in there and they’ve also been able to use that technology to look at the the energy systems the mitochondria of the cells haven’t they and so they’ve been able to say that he was wrong in that aspect that there was actually something wrong there that they were broken do you want to just go into that a bit

Mark Lintern
Sure. OK, so so yes, I mean, this is still a contentious issue, but as technology is improved, we can obviously discover more detail from within the cell. So there is contention over, let me just go back to the actual process. So Professor Seifried in particular suggests that defective oxfoss or the energy, the oxygen energy pathway within mitochondria is defective. And that is the consistent aspect of the disease. Now, from this, he explains that that results in the transition, the energy transition we see and the reliance upon glycolysis. And the problem with that is that other scientists have noted that oxfoss, the use of oxygen energy creation, is still operational to different degrees in different cancers, which suggests that this pathway, this oxfoss pathway, isn’t defective in the way being presented by Otto Warburg and maybe Professor Seifried. So there’s contention over that, which is a big issue. There are many other aspects of mitochondria that could explain why oxfoss is defective, such as cardiolipin abnormalities. But then we would expect also to see mitochondrial DNA damage, a pattern within mitochondrial DNA, pathogenic mutations that would also help to explain this defective process, this defective oxfoss. But we can’t, as of yet, those mutations don’t appear to be present. So there are several damaged aspects of mitochondria that are present that we can see that are suggestive that oxfoss is not working and would could explain the reason why it’s working, not working. But again, this is in contention because other cells that, so for instance, there’s a disease called Bath syndrome, where cardiolipin abnormalities are also apparent. So you have a similar process that occurs, seems to occur in cancer cells in the or rarely go on to develop cancer. So there’s quite a number of contentious anomalies associated with this. So it appears as though oxfoss is still operational and it’s not the underlying mechanism as is being suggested. Interesting.

Robin Daly
So you’re saying that while it’s still being debated, this question, your own conclusions from what you’ve looked at are that that’s not the case that there is a damaged system there.

Mark Lintern
Yeah, the system is, it clearly is damaged there, however, there is no specific pattern of damage that can explain why oxfoss would not be operational or defective in the way that’s being presented. And all the scientists have shown on many studies that oxfoss can be reinstigated under conditions of nutrient deprivation. And certainly with Professor Losanti’s work, he has shown that by targeting the oxfoss pathway in particular cancer cells, such as cancer stem cells, you can kill these cells, which indicates that there is an alliance on oxfoss, the oxfoss pathway in certain cancer cells.

Robin Daly
Right, so it’s a similar picture to the somatic mutation theory in as much as that there is damage there, you can find genetic damage and everything, but you can’t link it up, you can’t make a link between what you find and the outcome.

Mark Lintern
Yes. I mean, there’s a hierarchy to how the human body works. It has to work in a particular foundational approach. So you would expect to see a particular pattern of damage as scientists were looking for with a somatic mutation theory and as they are with the metabolic theory, you would expect to see this pattern occurring. So you could then treat the disease in any particular way or predict how the disease would form. At the moment, it appears as though there’s randomness. So there’s randomness between the metabolic theory and the somatic mutation theory in the sense that there appears to be no particular pattern of damage that can specifically identify the mechanism that’s causing oxfoss to operate in this particular way. That’s the sticking point for me.

Robin Daly
Yeah okay well good so at that point in your journey then you’ve come to the conclusion that Hallmark 7 is very important and you said that actually a lot of the other hallmarks are kind of downstream as you put it from Hallmark 7 i.e their consequences of the energy system going weird that this generates some of the other hallmarks so therefore it’s a kind of kingpin hallmark that in terms of the disease if you knew what was going on there you’d know an awful lot about the disease basically. So that’s really important so you’ve identified it’s this kind of kingpin hallmark but also you’ve identified the fact that nobody has got a decent explanation for why it happens none of the theories can explain it.

Mark Lintern
Yeah, so the metabolic theory does come close, but as we were just talking about, there is no pattern of damage that could essentially confirm why ox was operating in the way there is. So that then led me to the to the notion that, okay, this is, like you say, a significant hallmark, and because most of the other hallmarks appear to be a downstream event of abnormal metabolism, which is obviously key to the disease, it warrants us investigating possible other causes of this particular hallmark. And if we can potentially find other causes of this particular hallmark, the Warburg effect, then just maybe that could be the underlying mechanism driving the disease. It’s at least going to take us closer to that.

Robin Daly
Yeah, it makes sense. Yeah. Okay, so off you went in a journey to look for what could be generating the Waldberg effect, yeah?

Mark Lintern
yet. But at the same time, what we’ve got actually accruing here is the realisation in my head that randomness cannot cause consistency. And I’m looking for the consistency of the disease. And the abnormal metabolism was one. And it was clear that there needed to be an explanation for the Warburg effect. This is key. But also you have, like you mentioned earlier, the involvement of many different carcinogens. And they all, to varying degrees, cause varying different levels of damage, random damage. Yet these carcinogens appear to be able to stimulate or generate the consistency of cancer. So that was another sticking point. This is another random factor associated with the disease that appears to be able to create consistency. And that didn’t sit for other possible explanations for the Warburg effect. I was also, in the back of my mind, thinking, well, there has to be some sort of consistency associated with carcinogens and the many different toxins that can generate the disease and the many different levels of damage that seem to generate the disease. There must be a consistency there. So it wasn’t just essentially that I was looking at metabolic theory and abnormal metabolism on, singularly on its own. It was all these, all this information was accumulating together. And I was trying to essentially explain cancer from many different angles, but through this funnel of consistent behavior.

Robin Daly
It’s interesting is there’s so much information out there and so many aspects to look at that I can imagine your attention being drawn here, there and everywhere and the real need to find a direction and a focus in order to drive you forward in a meaningful way. Very interesting and yeah this investigation of Hallmark 7 I really like your drive to try and explain the consistency of the disease in this way and not accepting the fact that all these weird and wonderful things could all have the same effect on us without there being some consistent factor which funnily enough what you’re saying is exactly in line with what Warburg was saying that you know all these things he could call them distractions I think from the most important part of the picture he found something which was consistent actually the Warburg effect was very consistent and as you’ve pointed out now actually generates most of the behaviors of the disease anyway so trying to explain that makes complete sense and trying to explain it in a way which isn’t trying well if you like it’s trying to bring together all this mass of diverse information and causes and find an umbrella under which they can all sit is we’ve got to do that we can’t just go on making cancer a more and more and more complex disease which is what we’ve done all throughout the 20th century and well into this century we’re just finding ever greater complexity and more variables to deal with all the time and you’ve kind of gone the other direction you’re looking for one thing rather than you know finding the the thing that actually creates the consistency rather than diving ever deeper into these increasing number of variables that are being dealt with by computers mainly these days the only things can do it

Mark Lintern
Absolutely. But I would say I wasn’t at the beginning, I wasn’t looking for one particular course. The thing that was driving was again, this consistency. So that is where the funnel has essentially occurred in driving this idea that there could be a specific cause. But it wasn’t that I set out to think there was one cause and therefore I will try and prove that it was the randomness. The randomness didn’t make sense when it did the consistency. And then it’s because of that drive to identify the consistent factors that are associated with the disease that then kind of pushed me down this avenue of identifying a particular or coming across a particular aspect of the disease that appears to be more singular than it is multifactorial in that sense.

Robin Daly
Right. Okay. Well, look, we’re going to leave it there. We’re done for time. And we’re going to pick it up again next week at that point. We’re going to go into your exploration of the Warburg Effect and how it could happen, what things could be driving it. So, really good talk today. Thank you very much, Mark. And look forward to the next one.

Mark Lintern
Thank you Robin, speak to you soon.

Robin Daly
I hope you’re enjoying joining me in this amazing journey through Mark’s train of thought of more than eight years. It’s fascinating stuff and I have to say as a non-scientist I completely love his sort of common sense approach to things such as keeping a firm hold of basics like the unlikelihood of a consistent, predictable disease like cancer ever arising from a totally random set of circumstances. Part 3 will be broadcast next week so do make a note to join me again here.