The Peter Attia Drive - #30 - Thomas Seyfried, Ph.D.: Controversial discussion—cancer as a mitochondrial metabolic disease?

Episode Date: November 26, 2018

In this episode, Thomas Seyfried, a cancer researcher and professor of biology at Boston College, discusses a controversial view of cancer as a mitochondrial metabolic disease. Many topics related to the causes, treatments, and prevention of cancer are covered in this in-depth conversation. We discuss: How Tom got interested in cancer research [9:00]; Calorie-restricted ketogenic diets, fasting, and epileptic seizures [18:30]; Otto Warburg and the Warburg effect [30:45]; Germline mutations, somatic mutations, and no mutations [42:00]; Mitochondrial substrate level phosphorylation: Warburg’s missing link [51:30]; What is the structural defect in the mitochondria in cancer? [1:02:00]; Peter’s near-death experience with the insulin suppression test while in ketosis [1:06:30]; Insulin potentiation therapy and glutamine inhibition [1:13:15]; The macrophage fusion-hybrid theory of metastasis [1:39:30]; How are cancer cells growth dysregulated without a mutation? [1:47:00]; What is the dream clinical trial to test the hypothesis that we can reduce the death rates of cancer by 50%? [2:03:15]; How can the hypothesis be tested rigorously that structural abnormalities in the mitochondria impair respiration and lead to compensatory fermentation? [2:26:30]; Case studies of GBM survivors [2:32:45]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterottiamd.com. Hello everyone. Welcome to this week's episode of the Peter Rattia Drive.

My guest this week is Professor Tom Seyfried, who many of you will know, but I suspect an equal number of you will not know. Tom has come to us through many channels, meaning the requests to speak with Tom have come on many levels. There's been a lot of requests through social media, through the site. And of course, based on our discussions with Dom D'Agostino, Tom has been front of mind for quite a while. This is my first time meeting Tom, but I feel sort of like I know him because I've read so much of his work. And Bob Kaplan, who of course you all know as my trusty right-hand guy who lives in Boston, actually takes a course from Tom and he's taken a course in the past and continues to just wander around

Tom's office and just hang out with him overall. So in some ways this felt kind of familiar, though it was my first time meeting Tom. Tom's background is that he's got a PhD in genetics and biochemistry from the University of Illinois. He got that in the mid seventies and a bunch of other distinctions that I'm not going to go into because we're going to link to all that stuff. He did his postdoc in the Department of Neurology at Yale, and it was there that he first became interested in ketones because of their application in the amelioration of recalcitrant seizures. As we get into in the episode, that led to his interest in cancer,

which is now his focus. Tom has published over 150 peer-reviewed publications. He's the author of numerous books, textbooks, et cetera, including kind of a treatise on this. So his magnum opus is effectively a book called Cancer as a Metabolic Disease. I probably got my first copy of this a few years ago, and in many ways, that's what sort of felt quite familiar in speaking with him. He's currently a professor at Boston College, and his research today focuses on the mechanisms by which metabolic therapies can manage chronic diseases such as epilepsy, neurodegenerative lipid storage diseases, and above all, cancer. In this episode, we talk about Tom's background, as I sort of alluded to, his work in epilepsy, neurodegenerative lipid storage diseases, and above all, cancer. In this episode, we talk about Tom's background, as I sort of alluded to, his work in epilepsy and how that

led him to the interest in caloric restriction and ketosis. We revisit the man, the legend, Odo Warburg, and talk about the Warburg effect and Warburg's point of view on these things. And I do push him a little bit on this because I want to point out that it's not entirely clear amongst people what the Warburg effect really implies and how ubiquitous it is. And I have to be honest with you, I don't necessarily share Tom's views on a number of these things. So I wanted to do my best to sort of represent as many other views as possible. But at the same time, I hope the discussion is helpful. We get into a bunch of the semantics. I knew this was a very technical topic, and I know that not everybody has the luxury of listening to this while they're reviewing the show notes. So we do go over the differences between respiration or oxidative phosphorylation and fermentation. It's very

important to understand this. So one thing to keep in mind with this podcast, and frankly, any of the more technical episodes we do, if you're struggling with a concept, hit pause. I don't think it's worth sort of going through these, not understanding them. I think it's cool to listen to this, hit pause, go back, hit Wikipedia, ping us with a question on social media or whatever, if there's a concept that's stumping you. But this is obviously going to be one of the more important concepts. If you can't understand the difference between respiration, oxidative phosphorylation, as it were, and fermentation, then a lot of this won't make sense. We also get into this idea of substrate level phosphorylation, a very important concept, and the fermentation of glucose. We also talk a lot about glutamine. This is something that I haven't spent a lot of time

talking about in the past. I think I do touch on it a little bit with Dom D'Agostino, but we get into it in much greater fashion. And we, of course, get into ultimately the fundamental question that I think people who are interested in metabolic therapies for questions have to be able to answer, which is, is cancer primarily a metabolic disease, meaning a disease whose origin arrives in the mitochondria or in the metabolic machinery of the cell? Or is it primarily a genetic disease where sometimes you will and sometimes you won't sustain mitochondrial damage? Now, I have to, you know, and you'll see this in the interview, it's not entirely clear to me that I buy the argument that cancer is entirely a metabolic disease, though, as some of you will

know, I am very bullish on the use of metabolic therapies in cancer, but I'm also very bullish on the use of immunotherapy in cancer and, when appropriate, chemotherapy in cancer. So, you know, my view is that cancer is about as hard a disease as there is ever going to be to target, and therefore we ought to turn our attention to as many legs of the stool as possible and not just one. I think the discussion gets a little bit heated at one point when I take issue with something Tom said about suggesting that biopsies could exacerbate cancer. I really don't want anybody to come out of this believing that having a biopsy is going to increase their risk of metastatic cancer. I think that anyone's entitled

to a hypothesis, but to my knowledge, there are absolutely no evidence to support that claim. We talk a lot about a particular type of cancer called glioblastoma multiforme, GBM, also known as a grade four astrocytoma. This is, of course, a cancer that if you haven't heard of it, you've certainly heard of its effect. John McCain, who recently passed away, suffered from this. I lost a friend to this when I was younger. And I think that if you know somebody who has died of brain cancer, the chances are there's a pretty good chance this is the cancer they had. This is one of those cancers that gives cancer a bad name. And in all fairness, I don't think there's ever been a true documented survivor of this cancer.

In all fairness, I don't think there's ever been a true documented survivor of this cancer. It also may provide one of the more interesting model systems to study metabolic therapies for cancer. I guess the most important thing we close with is I sort of push Tom a little bit on what experiment he would want to see or do to advance the thinking in this field. In many ways, Tom's a little bit of a guy that's on the sidelines of, you know, sort of mainstream cancer. These views, these metabolic fuels, unfortunately, unfortunately, in my view, don't get the attention they deserve. And, um, other people that I'm going to be talking with in the future, such as Sid Mukherjee and Lou Cantley are going to be some, I think some of the

people who are now starting to see through their own research some of the potential applications for these things. And so I think that in many ways, the problems that Tom has been working on for the last 30 or 40 years are very slowly beginning to gain acceptance. And I don't like to use the word mainstream, but I think you know what I mean, in the more mainstream circles of oncology. This interview does get technical at times. And so as is the case with virtually all of our interviews, please pay attention to the show notes if you're having difficulty, if for no other reason than the fact that a heck of a lot of work goes into preparing them on the part of our analytical team. If you like this podcast, I would ask of you very kindly

to go and leave a review at iTunes. And I suppose if you don't like this podcast, you can also do that. Lastly, if you are interested in receiving a weekly email, which comes out every Sunday morning from me, that usually talks about something I've done that week, something I've learned that week, something that is hopefully of interest to you, by all means, sign up for that at peteratiamd.com. And I think that's pretty much all I want to say as we go into this. So with that said, please give it up for my guest today, Dr. Tom Seyfried. Hey, Tom, how are you? Well, thank you very much. Well, thank you so much for making time. I know you've got a long lineup of students outside your office here who are kind of pissed at me for

sitting here taking up time when you could be answering their questions. They'll recover. You know, a lot of people have been sort of reaching out to me on social media and saying, you know, you've got to have Tom on, you've got to have Tom on. You know, the podcast with Dom was excellent, but there's so much more we want to understand about cancer. And, you know, certainly cancer is something near and dear to my heart. I did my fellowship in oncology, but at the same time, I think I understand cancer far less than I understand things that I didn't formally train in. I think I have a better understanding, for example, of heart disease than I do of cancer. So I'm really excited to explore a lot of topics today and acknowledge

that we probably won't even scratch the surface of all that you think about. But all that said, how did you get interested in this? We started it when I was at Yale University, Department of Neurology, where we had been working on epilepsy and lipid storage diseases and gangliosides, basically, the complex lipid molecules. And one of the individuals that I was working with at that time, Robert Yu, was my mentor at the time. He had done some research on ganglioside changes in tumors. And we had been looking at that. And I said, there was some interesting molecules in those tumor cells. So I also knew Dennis Spencer, who was the chief of neurosurgery at the time at Yale. And he said, why don't you come up to the

operating room with me, and I'll get you a nice piece of glioblastoma from a patient. You know, I'm a basic scientist. I'm not a clinician. I don't know what's going on. So I said, sure. He come into the operating room and it was kind of an experience that I'll never forget, having someone take a tumor out of someone's head. And they were asking me all kinds of questions like, you know, do you think we should put pellets of radiation in the cavity and, you know, all this kind of stuff. And of course, I didn't know. I said, I'm here to look at the ganglion side pattern in the tumor. I don't know how to treat the cancer or anything like this. But any event, we had then started making our own brain tumors in the mouse based on the work of Harry Zimmerman, who started the

first school of neuropathology in the United States at Yale University in the back of the 1930s. And he was still alive at the time. He lived to be 98 years old or something. So I was interested in doing comparative studies of glycolipids in human and mouse brain tumors to see whether or not we can come to some common changes. And that's how we got started, pretty much looking at comparative biochemical profiles between human tumors and mouse tumors. And there was some similarities, but there were many differences as well. But we didn't get into the kind of therapeutic evaluation of these tumors until we also had a

huge program in epilepsy, mapping genes for epilepsy. We did a lot of things at Yale. I was working on the glycolipids of the tumors, glycolipids of developing brain, lipid storage diseases, and epilepsy. And I wrote a grant internally at Yale, which was rejected, asking about ketogenic diets. And what year was this? This was back in the late 70s, early 80s maybe, 1980. And they said, oh, nobody's interested in ketogenic diets.

It's kind of passe. This was before the work at Hopkins or? Yeah, Hopkins, John Freeman was a friend of mine too who was the godfather of ketogenic diets. He was the one that saved Jim Abrams' son, Charlie. And Jim was a movie director. And his friend, Meryl Streep, made the movie First Do No Harm, which was based on, in part, on Jim's experience with his son. But I wasn't connected at that time to Abrams or any of

that stuff. That was even before the Charlie Foundation. I just had this inkling that maybe ketogenic diet would be interesting to test against some of the epilepsy models that I was working with. But does that mean you suspected that something to do with glucose metabolism was? No, nothing. I just thought it was an interesting approach to a non-drug approach for seizures. And anyway, the grant was summarily rejected. So I said, well, nobody's interested in this. So I left Yale and I came up to Boston College here to start a program. And then we were here from, then it was 10 years, 15 years later, we developed some of the best animal models for epilepsy. And we were looking at brain to biochemistry and epileptic seizures and the genes that caused epilepsy. And then one of my PhD students, Mariana Tran, says, oh, they're having a big meeting out in Washington on ketogenic diets for epilepsy,

and maybe our model would be appropriate for this. I said, nah, this is, you know, I says, after my experience at Yale, I said, nobody's interested in this crap anyway. You're still traumatized by the grant. Yeah, so I said, they're not, you know, I got to summarily reject it. It says, this is, nobody interested in ketogenic diets. So anyway, she said, hold on a minute. So I said, I had a few extra bucks in the grant. So I said, okay, go on out there. In fact, she wrote a little blurb and they funded her to go out there.

So she comes back and starts telling me about, wow, you can't believe what I saw out there. All these guys are interested in this ketogenic diet. And this guy, Jim Abrams, and he wants to start this foundation called the Charlie Foundation. And it was like to study epilepsy and ketogenic diets and stuff. So I said, all right, what the hell? So we started to put them on the mice.

And it was funny because we didn't know what we were doing. But then at the same time, two things came together at the same time. We were studying gangliosides for lipid storage diseases. And there was a drug company over in England that gave us this new drug that was supposed to stop ganglioside synthesis and therefore reduce the storage in the brain. Of course, at that time at Boston College, they didn't charge me for animals, which they do now, which is a tragedy because you can really do a lot of work. The damn mice cost so much money and there were so fewer restrictions. I mean, we'd followed all of the animal care protocols, but we had access to a

large number. So we could do experiments that you couldn't do anywhere else. So when we got the drug from the company, we were feeding the drug to the mice, and we looked at the ganglion. Yeah, it's really down. But so was the body weight. And then when we put the control group in, we found out that, yeah, the tumor shrunk and the ganglion size were reduced from this drug. But then the body weight was also reduced. And the controls were also, they're both animals being fed ad libitum?

Ad libitum. One had the drug, one didn't. Okay. So the drug somehow either reduced intake or increased expenditure. We don't know, but the body weights were reduced by about 15 or 20%. And the tumors were significantly reduced by about 50, 60%. So I told the company that, you know, I just threw them on. I just, this was a pilot study.

I told the company that your drug seems to really shrink brain tumors. They go, wow, Jesus, this is a much bigger market than, say, Tay-Sachs disease, right? So that's when they gave me $200,000 to investigate the mechanism by which their drug was stopping brain cancer, because I showed them the data, and they were all excited. So we then began to investigate this, and Dr. Mukherjee, who worked, started with me. I said, hey, I hired her specifically to start looking at this. And then when we realized that, you know, what's working? She said, you know, a lot of times these drugs work through calorie restriction. So I said, well, why don't we put a control group? We all decided, let's put a control group for body weights.

And then we just, one was the guys with the drug and losing weight. The other guys would just take the food away from them. So the body weights would be absolutely identical. So they were pair fed. Wasn't pair fed. One group was eating ad libitum and they were losing body weight. And the other group- Oh, I see. Okay, I got it. We had to restrict the calories- To match their weight. To match the body weight. So they were pair weighted. Yes, pair weighted. Yes. And then we evaluated this and the tumors were exactly the body weight. So they're pair-weighted. Yes, pair-weighted, yes. And then we evaluated this, and the tumors were exactly the same size. So it had nothing to do with the drug.

Even though the drug was working on the targeted molecule, it wasn't the targeted molecule that was responsible for this. So that's when we also decided, with the epilepsy overlapping, does the ketogenic diet work through calorie restriction? Because many of these children that get ketogenic diets, they have a very restricted calories. And you have to give very small, you can't let kids eat massive amounts of fat. Because invariably, John Freeman told me the diet doesn't work if they just like, one out of two or 300 kids just loves to eat all this fat.

And the seizures don't go away. Like one out of two or 300 kids just loves to eat all this fat and the seizures don't go away. So we- In other words, the thinking at the time was there is some amount of caloric restriction that is necessary within the context of the ketosis to also affect the epileptic seizures. Yes, absolutely. But you have to be very careful because many of these children are on the growth spurt. So you have to be careful on how much restriction you give. And the other thing, of course, it's self-restricted. There's several physiological systems in our body that when you

eat a lot of fat, you just don't eat a lot of calories. It's a turnoff. It works through the vagus nerve. The hormone cholecystokinin is kind of an appetite suppressor. It affects the vagus nerve, which then stops the appetite. You don't eat as much. So I have so many stories. So I was sitting on a bus one day. You're on the right podcast, Tom, because we don't have time restrictions. Yeah, but listen. So they made this thing called the vagal nerve stimulator. And it was made by a company.

I can't remember the name of it. Made a fortune. They would implant the stimulator into the persons who has epilepsy. And it would send out things to stimulate the vagus nerve. And I was sitting on the bus with this guy from Norway and he says, I said, you're putting this in the patient? Yeah, we were putting this in the patient. How does it work? Yeah, it seems to work really good. I said, how much is it? He says, well, the operation is like $4,000,

but the device, it was like 15 or $16,000. But they was putting them in all these epileptic patients and their work. I said, how does it work? He said, I don't know, but it works. So I said, I didn't know. I'm sitting on the bus. I don't know. We're going to MGM Studios down in Florida. And they closed the whole place down in the middle of the week in December so that they could attract all the epileptologists to use their device to put into these patients. It's one of these kind of things. So anyway, it comes back when we were working on ketogenic diets and calorie restriction, you know, we realized that humans have this internal system to stop calories. And if you don't stop the calories, invariably, you don't get the management of the seizures.

So we, in our parallel studies in epilepsy with mice and cancer and all this other stuff, In our parallel studies in epilepsy with mice and cancer and all this other stuff, we started to learn what's working in the patients. How do we translate what's working in the patients into the mice? The mice can be another source of information that we can feed back. And we published this big paper on calorie restriction, that the ketogenic diet was working largely through calorie restriction. And maintaining low blood sugar levels was the key to maintaining control of seizures. Now, I don't know if you did this experiment,

but if you took animals on an equally low caloric diet that was not ketogenic, so let's just say a very high carbohydrate, low fat diet, where presumably glucose levels would be higher, even though they would still be calorically restricted, would you get the same anti-seizure benefit? The same results, exactly. Because what was happening is that when the body is restricted of calories, you then make ketones. So the level of ketosis was also seen in the calories. It would be like a human doing water-only fasting. So how calorically restricted did they need to be if they were not on a ketogenic diet?

40%, 30 to 5 to 40% restriction. And then we did some studies in another group. We found out that 35% to 40% restriction of calories in the mouse equates to a water-only therapeutic fasting in humans. And that's because the- Yeah, their metabolism is- Right, seven or eight times higher than that of a man. So humans can achieve much higher ketosis than a mouse can.

than that of a man. So humans can achieve much higher ketosis than a mouse can. And the mouse, one week, a one day water only fast in a mouse is like a seven day water only fast in a human. And the blood sugars go down, the ketones go up. IRBs don't allow you to fast mice that long anymore, do they? Oh yeah. As long as they're healthy. Calorie restriction is generally a healthy thing. You don't want to over-restrict because then you're put into a nutritional imbalance and you don't want to go to the level of what we call starvation. This is another. Calorie restriction is healthy up to the point where you start breaking down muscle. If you start breaking down muscle, then you enter into a new physiological state called starvation. And that's very pathological. You don't ever want to go to that digression.

So some people, they get so carried away with water-only fasting, they can enter into starvation mode. I know this for a fact because I used to spend a lot of time with George Cahill, who used to run the Joslin Diabetes Centers down here in Boston, and he and I would talk for hours and hours with Bud Veach at the NIH about how long people can go with this transition over from therapeutic fasting into starvation. And also the body builds. It's like anything. Your body gets accustomed. You can go a long time without eating if you're in shape, if you've done this. But it depends on what your body weight is, how old you are. It depends on a lot of different things,

how long you can go without eating. But the bottom line is that we were trying to develop a therapy and figure out the mechanisms by which ketogenic diets were therapeutic. Now, going back to the Cahill stuff for a moment before we come back to that, did you have a sense or did George have a sense of when those patients are in a negative nitrogen balance? And I assume it matters as to what their starting weight is and muscle mass and things like that. But were there general rules about once you cross over that point where you're basically pulling nitrogen out of the muscle?

Right, right. And he got those data actually from the 10 guys that starved to death in May's prison in Northern Ireland. Bobby Sands in that group, actually. He was there monitoring their blood work while they were dying of starvation. These were prisoners that they were fasting as a protest, correct? Yes. They made a movie out of it, Every Mother's Son, about that there was 10 Irishmen that were- How long did they live on average?

They averaged, I think he had the data. He was never able to publish it. The British government was on top of him about that. But he was able to collect the data and shared some of that stuff. And it was very interesting. It's a horrible thing. It's like one of the worst ways to die is starvation. So what happens, your diaphragm is the last muscle that will be digested. And there's a momentum that starts.

Now, you have to realize that these guys that did this. So they don't die of just acidosis. It's actually the diaphragm. They're drowned in your own body fluids, basically. Jeez, it's brutal. So because what happens is once your diaphragm can't work, your lungs fill up with fluids and you drown in your own fluids. And the diaphragm presumably stops working because of either the loss of muscle or the

electrolyte imbalance. Yeah, both, a combination of both. And then you can't stop it. Once the momentum starts- It's like these horrible hiccups, right? Yeah. Well, once the momentum starts, it seems like they tried to do an intervention on a couple of the guys, and they weren't able to reverse it.

So it was pretty horrific. Now, those guys were all young Irishmen in their 20s and 30s. I don't know what the oldest guy was. But they lived from, I don't know, 68 to, I don't know, 85, 90 days without any food, just water. But then he subsequently fasted these very obese people. For 40 days? Longer, for six months, eight months. Oh, wow.

Yeah, he has the data. One guy, a postman, lost his job, weighed 450 pounds or something, couldn't deliver the mail. So they put him on the water-only fasting for six months, I think, six or eight months. Guy lost 250 pounds. This is different from the guy who, there was a single case report of a patient who weighed a little over 400 pounds and did a 382 day fast. But I didn't realize that was Cahill that was overseeing that. I don't know if that was Cahill. There was another, there's a couple of them. But he was overseeing, he showed us the data on this one guy, the postman. And the issue of course is is I don't know if he took many supplements

because your body fat holds a lot of vitamins, fat-soluble vitamins. The minerals come from your bones. The liver control holds an awful lot of B vitamins and things like this. I think there were supplements over the course, but they weren't. You don't need a lot of supplements. Your body holds a lot. We evolved as a species to starve. I mean, our existence today is dependent on our ability to go long periods of time without eating. We don't receive that anymore. Yeah, yeah. And it seems that our ability to access minerals and vitamins is highly dependent on our nutritional state. In other words, your need for those things tends to go up in a fed

state, at least according to some research I've seen. Yeah, you're right. And our ancestors were hardened people. Their bodies were already acclimated to a starvation mode. So they were very efficient in maintaining mineral and nutrient balances. I think in our society today, and this is purely speculation, I think a lot of the foods are depleted in the kinds of nutrients that we would need. Therefore, some people are almost like in a starvation mode, but they're eating food that has no nutritional value. And consequently, you store a lot of fat. Because the body doesn't usually get rid of sugar. As I said, sugar is stored.

It's not, you know, pee out sugar unless you have type 1 diabetes or something. The body has all these filtration systems to keep carbs, which is then transferred to fat and stored as fat. That's our energy to keep us alive when there's no food. But all these ideas and things were developing when we were doing the epilepsy studies. And it became clear that calorie restriction was a key mechanism by which the ketogenic diet was working. And we have since then seen in numerous children with epilepsy that breakthrough seizures will occur when blood sugar spikes. Define spike in that very specific case. How high does it need to be in milligrams per

deciliter? Yeah, it doesn't really, for managing epilepsy, there's many cases where it just has to go a little bit above the baseline. So kids will have a very low 70, 68, 65 milligrams per deciliter. They'll grab a cupcake at a party or whatever and spikes up to 120 or whatever. And then you'll get a breakthrough seizure. And do you believe that it is the absolute value of 120 in that case? Or do you believe it's the D by DT, meaning the rate of change of the glucose? We can't know that. It hasn't been done effectively. All we know is from the clinicians and the nurses that have told me all this information. And of course, when your child has a breakthrough seizure, nobody likes to see a kid seizing.

I mean, it's traumatic. It's not a pleasant thing. Nobody likes to see a kid seizing. I mean, it's traumatic. It's not a pleasant thing. So once they realize that the kids have to maintain this very stable, the parents are very, very restrictive of these kids because they don't want to see their child seize. So they're very restrictive. So when we do the same thing for cancer, the problem with cancer is you don't see a breakthrough seizure. You don't see a group of tumor cells starting to grow faster.

You don't see the immediate effects, but they're there, but you just can't see them. With epilepsy, you have a very visible, clear indication that something went wrong. And invariably, there's a spike in glucose. Now, what's very interesting is in these kids, they could be maintained for months without a single seizure. And then one drink of a grape juice or whatever the hell, boom, breakthrough seizure within sometimes minutes from the time you took the, so it's a very, they can flip back, but then they can also get back on track again. They don't have a large number of seizures. They can just, they can get back on track. But it's a very

sensitive system in our brains. Then as John told me, John Freeman, he says, we don't understand that if a kid is maintained seizure-free or minimal seizures for long periods of time on ketogenic diets, and then we remove the diet, they seem to be managed. In other words, they don't return to their multiple seizures that they would have had every day. So he doesn't know if it was because the diet did something fundamental or they outgrew the seizure or whatever. It was, again, these are areas in epilepsy that are under active investigation by a lot of- But it's interesting. It's almost like a reset, right? I mean, one of the things that impressed me about reading the case studies of these very, very long fasts is that in the reports that are

published several years later, many of the subjects maintain their new weight reduced state, which is a bit counterintuitive based on what we know today about, you know, traditional dieting approaches where everybody sort of, you know, will return back to baseline. And so it, it begs the question, right? When you starve this person for six months, do they completely change the way they eat on the other side because of a behavioral shift or is it a physiologic shift, meaning their metabolism has been kind of quote unquote fixed? Yeah. Well, I think it's probably a combination of both. I mean, again, these are very complicated physiological processes.

You know, they call it the thrifty gene. That was a term. It's not one gene. It's like the thrifty physiology. If you do yo-yo dieting, I mean, you can be screwed up for a long period of time. Those things all have loose ends. There's nothing that we have found that's absolutely consistent in all patients all the time when it comes to those kinds of things. And that's why they're always interesting to talk

about because someone always has some new people, new idea about something that they've seen. It kind of fits in a little bit with what everybody else is. I don't really dwell, engage in those kinds of things as far as our research is concerned. You know, we know about them. We talk about them, but we don't, other than the calorie restriction that we introduce into the mice. And then when we found out that the calorie restriction and the ketogenic diets were working. So people say, well, why don't you just do calorie restriction? Because,

you know, cancer, back to cancer, we don't like to restrict. The term restriction, even the term, you already got a disease, now you have to be restricted. You know, it's like, so ketogenic diets are a little, takes the sting out of a therapeutic fast. And they can also replicate some of the same physiological changes. The key is to lower the blood sugar and elevate the ketones. And that's what ketogenic diets do for managing epilepsy, and they do the same thing for cancer. The issue, of course, is we don't know the mechanism by which lowering glucose and elevating ketones is responsible for the management of the seizure.

This is under an active investigation by a lot of labs. The actual mechanism, is it the elevation of the ketones, is it the reduction of the glucose, or is it some combination of the two? But for cancer, it becomes very clear. The mechanism of action is very clear for how this kills cancer cells. It's based on Otto Warburg's theory. So when we started to do this and realized that calorie restriction was shrinking these tumors down massively, you know, based on the drug that I told you about, because it

was working through calorie restriction. Then I said, you know, how is calorie restriction stopping tumors? And then we realized that it was lowering blood sugar. So we started measuring blood sugar in these calorie-restricted mice and measuring ketones. And we were seeing that we were getting these major shifts. And then we said, you know, then it became clear who was the guy who did this or thought about, and it was Warburg. Now, he wasn't doing ketogenic diets. Had he done and known about that, I think he would have been able to crack this cancer thing far earlier than it.

He didn't do ketogenic. He didn't know anything about that. So let's back up for a moment for people. I mean, I think most people listening probably know what the Warburg effect is and who Warburg was, but maybe just give us a moment of setting the stage for what his observation was that now bears his name. Well, his interest was in biochemistry. He was a classical chemist, biochemist in his time. And he began to

look at the metabolism of tumors. So he made an observation which was solidified that cancer cells continue to do ancient fermentation metabolism, even in the presence of oxygen. So this, the Pasteur effect from Louis Pasteur with the yeast was that yeast will ferment. They evolved. That organism evolved to be able to ferment, get energy in the absence of oxygen. But when as soon as oxygen came into the presence, they stopped fermenting and they immediately started respiring. They have a system that can do that. So the Pasteur effect was basically the termination of fermentation in the presence of oxygen. That was the Pasteur effect.

And it was repeated in all these yeast strains and this kind of thing. And that was a fundamental biochemical advancement, so to say. But Warburg recognized, he knew Pasteur's work very, very well. And then he said, geez, these cancer cells, man, they continue to throw out lactic acid even in the presence of 100% oxygen. So he grew cancer cells in 100% oxygen and they were still making lactic acid. So clearly the Pasteur effect wasn't working. I'll just interject for a moment to explain something to the listener and we'll probably have a picture of this, but of course you take glucose to pyruvate

in the cytoplasm. And that's a, you know, that yields a couple of units of ATP. And then you have sort of a choice of what you're going to do with that pyruvate. If your demand for ATP is incredibly quick, usually exceeding the capacity of oxygen to get into the cell, you'll make lactate. And that's also relatively inefficient, meaning you don't get that much more ATP. I think you get another two molecules of ATP per unit of pyruvate, but at least you have the advantage of saying I'm not limited by oxygen. Alternatively, if oxygen is plentiful, and more importantly, if the demand for ATP is not excessive, you can shuttle that pyruvate into acetyl-CoA in the mitochondria and you can generate over 30 units of ATP. And so what you're saying is there is an observation which said, hey,

if I put this cell in the presence of lots of oxygen, it really shouldn't make much lactate. Right. And that's what he finds when you take normal tissue like kidney slices or muscle slices or liver, you'd grow them in 100% oxygen and they produce minimal, barely detectable lactate. There's always some going to be produced in every tissue, but basically it's very minimal, very minimal. But the cancer cell continues to dump out massive amounts of lactic acid, even in the presence of 100% oxygen. So this was a phenomenon.

He saw this over and over again. It didn't make any difference whether it was a human tumor, a mouse tumor, rat tumor. They were all doing this same kind of thing. So what he concluded from this was that their respiratory system was defective. Because like you just said, now that's the Emden-Meierhoff pathway going from glucose to pyruvate. Pyruvate is the end of that. So then the opportunity is that the pyruvate would enter into the mitochondria under oxygenated conditions and be fully oxidized

to water and CO2. And oxygen is the acceptor of the electrons to form the water. And the carbons are coming from the foods that we metabolized. But the cancer cell was dumping out large amounts of this lactic acid. So why would a cancer cell dump out lactic acid? And it became clear to Warburg through a variety of experiments that the respiratory system was defective in these cells. Let's just clarify that. Many people, when they hear that, we think respiratory system. We think of lungs.

What you really mean is the mitochondrial machinery that undergoes what we call cellular respiration. The lungs are bringing in the oxygen. The oxygen and getting rid of the CO2 that enables mitochondria. That enables all the cells and a majority of our cells in the body to perform this very efficient form of energy production, which then frees up the cells to do their sophisticated behaviors. Liver cells do what they do, kidney cells, brain cells, they all do what they do because they have this very efficient energetic system that's working called respiration. The lungs are just the facilitators of the body to get the good air in and the bad air out.

So basically, the cancer cell was continuing to produce massive amounts of lactic acid, despite the fact that there was all this. So he was then looking at the mitochondria, noticing that there were some defects and these kinds of things. But he wasn't at the level of electron microscopy or this. He just made the- What year? This is in the 1920s?

Mostly late 20s, 30s, 40s, all the way up to the 50s. I think he stopped his research maybe in the early 60s. Now, he won a Nobel Prize, didn't he? Yeah. Was it for the description of this phenomenon? No, it was for the discovery of cytochrome C oxidase, which is actually one of the key enzymes in the electron transport chain. Our cells generate energy through respiration. So he was nominated other times, and there's still some controversy about how many times he had been nominated for the work on cancer, but never to achieve another Nobel Prize. But he was considered one of the dominant biochemists in the 20th century. And he had very strong ideas and very excellent quantitative measurements for this.

A lot of his work was reproduced by dozens and dozens of scientists. So that was the fundamental observation. But he then extended this to the theory that why are the cells producing all this lactic acid? Because the organelle that is supposed to be involved is defective. This led to a lot of controversy. What do you mean defective? How defective?

What do you mean defect? How defective? What do you mean? So much later, Pete Peterson from Johns Hopkins had done a magnificent job in collating all this information. And he found that in every kind of a cancer cell, no matter what kind of it is, there was some defect in the number structure or function of the mitochondria. And it could vary. So some cancer cells have very few mitochondria, but they look normal. Very few of them. Other tumor cells clearly have a lot of mitochondria, but they look abnormal. So whatever it was, it was something to do with an impairment of the respiratory system within the cell. And if the cell can't generate energy through normal respiration, then it has to ferment. There's no other way they can get the energy. So it became the Warburg effect, which everybody talks about, is one of the biggest problems in this whole thing. Because Warburg in his paper clearly said that aerobic glycolysis, or what they call the Warburg effect, is a secondary problem that's subjected to many, many variances in the environment. But

everybody focuses on this. He said the real issue is the damage to the respiration. And everybody says, no, respiration is normal in cancer cells. And why would they say it's normal? Because they started doing cells in culture rather than looking at the tissues themselves. And once you start doing culture work, you're taking cells from a tissue and separating them and growing them as if they were microorganisms in a culture dish. Well, this changes everything. They're no longer connected to each other. They're growing in some artificial fluid and they're doing things that they sometimes do and sometimes not do in the real world. So you make a lot of assumptions about things based on a system that itself is artifactual. So let me ask a couple of technical questions. Obviously, measuring the amount of lactate or hydrogen ion that's produced is a way to

give us an indication of how much anaerobic metabolism is taking place. What, if you're not in cell culture, how do you quantify the amount of aerobic respiration? You look at the amount of oxygen consumed and the amount of lactic acid produced. So if you're doing aerobic respiration, you're consuming a lot of lactic acid, a lot of oxygen and producing very little lactate. And then you can quantitate the amount of ATP being produced per millimeter, milliliter of oxygen that you consume. And according to this, this can vary from anywhere from seven ATP units to nine, depending on the system.

But Warburg used the number seven based on his data at that time. So you could calculate the total amount of ATP being produced in the cell based on its oxygen consumption and its lactic acid production. And Warburg, did he ever do this in situ? Yes. He did it in slices, and then he did it in cell culture as well. So he created some of his own problems as well, switching from one to the other. The concern that we have now is that many

cells in culture look like they're consuming a lot of oxygen. And they're making lactic acid, but they're consuming a lot of oxygen. So like you said- Suggesting that they're doing both, which is still a bit odd. Yeah, right. Well, that was Sidney Winehouse's argument. His argument was the cancer cell needs so much energy that respiration by itself can't be sufficient. So they have to ferment and respire at the same time. And that made everybody feel that, yeah, Warburg was wrong. They do have good respiration, but they just need so much more energy. They need to ferment at the same time. But the work from Pete Peterson showed

that they have defective respiration. So, I mean, they have defective mitochondria, structure, number, and function, besides many other studies have shown. So you know that they can't be doing oxidative phosphorylation or respiration because the very organelle that is needed for that is deficient in some way.

And that could be many different ways. As I said, there's no one, all cancer cells, all cancer cells have a defect in respiration. How that defect came about can vary from one type of cancer to another. So one has to recognize that. So not every cancer cell will have the exact same defect in respiration in the mitochondria. Some will have very few mitochondria. So they just don't have quantitatively enough organelles to do respiration.

But what seems to be there seems to be functional, partially functional. Other cells, as I said, are loaded with mitochondria, but when you look at them, they're morphologically abnormal. So structure dictates function. In biology, we know that structure dictates function. So if the structure of the organelle is abnormal, you know that the function of that organelle is not going to be normal. And is the idea that those mutations were acquired? I wouldn't call them mutations. They would call them defects. Now, you can have a mutation. In other words, the genome is unaffected in some of those cases? Yes, we've done that. We sequenced the entire genome of five different independently derived cancers from mouse, all derived from different origins. And we didn't find a single genetic abnormality, what we call pathogenic, where the mutation would actually have an effect on a

function. And we didn't find a single one. So that told- So let's take, maybe take a step back and for the listener again, we'll go over some of the basics of genetics, because I think that for many people, there's an understanding that, basics of genetics, because I think that for many people, there's an understanding that, I mean, by definition, a cancer has a mutation that renders it incapable of listening to normal cell signaling. Do you have a sense broadly of what amount of human cancers arise from germline mutations rather than somatic mutations? It's obviously very small, but I don't know what the number is. Well, they say it's about five% to 6%. Oh, it's that high. Okay.

You know, and you hear about them, the BRCA1, BRCA2, Lee-Fraumeni, P53, you know. Lynch syndrome, et cetera. Yeah, yeah. But when we looked into those so-called inherited risks, we call them inherited risk factors. None of them have ever been 100% penetrant, which means that every person having that gene must express. They're not purely deterministic. Yeah, they're not deterministic. And as Warburg said, there are many secondary causes of cancer,

but there's only one primary cause. The primary cause is the damage to the respiratory system. So if the inherited mutation damages the respiratory system of the cell, the probability of cancer is a real possibility. So because everybody who has leaf round, many tumors or BRCA1 tumors or whatever, they all have, they're all fermenters. So the fermentation metabolism is there in every cancer. But there are some people that have the exact same mutation that the other person has,

but they never develop a tumor because for whatever reason in that person, that mutation did not damage the respiration. Now, it could be an environmental suppressive effect or another gene in the genome that prevents the inherited mutation from damaging the respiration. We don't know that. So we only know that you don't get cancer if your mitochondria remain healthy. That's what we know. So that's an important, because that goes back to the prevention issue. You know, how do you prevent cancer? You prevent cancer by keeping your mitochondria healthy. How do you do that?

Well, you avoid, if you can avoid those risk factors, mostly from the environment, like viral infections, intermittent hypoxia, radiation exposure, carcinogenic exposure, all these different things. Every one of those things can damage respiration in a population of cells, then leading to cancer. Because we know of no cancer that has normal respiration. But when you grow them in culture, people say, yeah, they have normal respiration.

They're taking in oxygen. So therefore, Warburg's wrong. But when you look at the structure in the vivo, and you look at the tissues, and you look at the actual architecture of the tissue, invariably you find damage to the respiration, damage to the structure and function of mitochondria. So what the field has done is put more credibility into the results from cell culture work than into the actual tissues that people see and look under the microscope and look at. Because the Warburg effect was largely forgotten for many years after his initial observation,

right? Yeah. A lot of what he did was forgotten. And Pete Peterson was one of the few guys that kept the fire burning. Because as I said, when Watson and Crick discovered the DNA as the origin of the genetic material, but it wasn't only them. There was a whole group of other people that were doing it. They just weren't acknowledged as much.

Yeah, and then the field ran off into that. And they also knew that there were chromosomal abnormalities in some cancers. So it made it clear that, hey, you know, these genomic defects in the tumor cells are likely the real origin of the disease. So the whole field more or less shifted away from the traditional biochemical analysis to the more molecular biology analysis. And therefore, you find more and more mutations, more and more genetic defects, and all these kinds of things, leading people to believe that these were the causes of the disease. And a lot of really nice experiments were done where they would introduce mutant virus particles into cells, and they would integrate into the nuclear genome, and then you'd see the cancer cells become transformed into a neoplastic kind of a cell, giving the appearance

that this was a cause-effect. They didn't realize that those same viruses went into the mitochondria and blew out the respiration. So that wasn't even considered as possible. But if the viruses are doing that, presumably they're integrating into the genome? Yeah, well, they would do it both ways. They can do it a lot of different ways. So sometimes the viruses actually infect directly into the mitochondria. They produce proteins in the mitochondria that screw up the electron transport chain. Other times, the viruses integrate into the nuclear genome, producing a protein product that then disrupts the mitochondria. Either way, the mitochondria

are disrupted, whether if it's a direct effect of the virus replicating inside the organelle, or it's an effect of a product produced by the virus that then goes and disrupts the organelle. And this is what we're finding for the majority of these situations. So even the hereditary mutations that we look at, they disrupt mitochondrial function. And if they disrupt mitochondrial function, you're at risk for developing a neoplasm in that particular population of cells. There are some cancers that don't follow that, correct? I mean, aren't there some cancers that have normal mitochondria? We haven't found any because the evidence for that is that they're all fermenting. We haven't found a cancer that doesn't ferment.

So if the cancer is fermenting, it's obviously not respiring. If its respiration would be normal, it shouldn't be fermenting. As a matter of fact, Dean Burke did this kind of a study way back in the 50s. He went and looked at various kinds of hepatomas because there was an article that was published to say that there was this very low, slow-growing hepatoma that did not ferment, which was directly related to your question. But Burke, who was at the head of the NCI at the time, studied these things in massive detail and was able to show that the slowest growing tumor did

have a significant elevation of lactic acid production over a normal cell. But you had to look at it really carefully and do the experiments over extended periods of time. So even the slowest of the slowest growing tumors, guys that would be maybe considered benign, were still making lactic acid. Another interesting thing was the crown gall tumors in plants. This is another interesting. Plants have cancer, but they don't metastasize.

They just grow these tumors. And people back in the 30s were testing Warburg's theory in these plants. And they all had damaged respiration. They were fermenting just like the mouse tumors. When you say respiration, you mean photosynthetic respiration? No, no. Plants have both. Plants can get energy from chloroplasts to build carbohydrates.

But they also have mitochondria. Oh, I didn't realize that. So their carbon fixation obviously comes from photosynthesis. Yeah, yeah. But when they make their equivalent of starch. Yes. So they will burn their own fuels to generate respiratory energy. But they also have dysmorphic cell growth, and they've called these crown gall tumors. You see them sometimes

on the side of trees and things. So people back in the day analyzed the biochemistry of these things. And they also found that they were following Warburg's metabolic profile, but they didn't metastasize. And the reason they don't metastasize is they don't have an immune system. And it turns out that from our work and the work of others, the metastatic cell is actually part of our immune system. So macrophages and leukocytes, these are the cells that have the genetic capabilities of moving around the body, entering into tissues. This is what they do. Plants don't have that. Plants don't have that kind of an immune system. So they don't metastasize. They grow in place. But humans and other animals, of course,

that have these cells of the immune system, therefore they can get metastatic cancer. So before we get to that, because I do have a number of questions about that topic, another argument that's been proposed for the Warburg effect is the need for cellular building blocks. The other thing that the tumor is doing above and beyond its non-tumorous cellmate is growing. And although not necessarily faster than a regular cell, it certainly grows in a less regulated way and therefore it's going to proliferate. So van der Heiden and I think Lou Cantley and Craig Thompson wrote that paper in 2009 that is, I'm sure you're familiar with. There's a science paper I believe.

And they proposed this other explanation which was, look, it's not just an energetic thing. In fact, I don't recall if they said it's not just or it's not even about the energetics. But the point here was this is where you get building blocks to make cells grow. Do you think it's possible that both of these are correct? Yeah. Well, you know, in the process of upregulating the Emden-Meierhoff pathway, you are going to get the carbons for building blocks. At the same time, you're going to get some energy. Now, through the pyruvate kinase system.

However, this is very interesting. But they deviate from the path from Warburg's theory in saying that respiration is normal. They think there's nothing wrong with the mitochondria. They've said that many times. Craig Thompson has said this. You have to ignore a massive amount of evidence to make those kinds of statements. You just have to ignore everything that Pete Peterson has done, which is a life's work showing that the mitochondria have knowledge.

But he doesn't mention that. They don't discuss Pete Peterson's massive amount of evidence. But you're right. In order for a cell to grow, you need a lot of building blocks. And you need carbon. Where's the carbon coming from this? And it's coming from both the pentose pathway and the glycolytic pathway. And it's also coming from glutamine.

So these cancer cells are sucking down glutamine. So you're getting the amide nitrogen to form the nucleotides. You're getting the glutamate that then goes into anaplerosis in the TCA cycle. So between glucose and glutamine, you are getting all of the building blocks that you need for rapid cell division. But where's the energy coming from? Okay, without energy, nothing grows. Nothing can live without ATP. So where is the energy coming from? And this is our thing. So we, myself and Christos Shonopoulos in Hungary, I proposed this a long time ago on a purely theoretical basis, having been convinced that Warburg was right, that the respiration of all cancer cells is damaged to some extent. So if that's the case, the Warburg effect was only the

glucose part of the puzzle. It wasn't the glutamine part of the puzzle. So now with our new information, we know that most of the ATP in the cancer is coming from substrate-level phosphorylation in the mitochondria, which is disconnected from oxidative phosphorylation. So what we have now is the missing link in Warburg's basic theory. So explain what SLP is. Substrate-level phosphorylation is the production of ATP when you move a phosphate group from an organic substrate onto an ADP molecule. So it's an ancient way of generating energy. In other words, it's an organic molecule that's an electron acceptor rather than oxygen. Right. So instead of going through the electron transport chain where you use NAD, NADH, NADP, NADPH as electron transporters.

Well, electron donors. Electron donors. You can do a very quick trick where you take an ADP and restore it, meaning it has two phosphates. You restore it to an ATP by using an organic molecule to donate a phosphate. Well, for substrate level phosphorylation. Yes, yes. So succinyl-CoA has a phosphate group on a serine inside the protein itself. And that phosphate group is then donated to ADP, sometimes GDP, make GTP, both.

Depends on the situation. But in cancer cells, it's ATP. So you're moving phosphate groups from an organic substrate onto the ADP as the acceptor. And you can generate massive amounts of energy from that process, which can replace the level of lost energy from oxidative phosphorylation. And does that occur inside the mitochondria, inside the inner matrix? Yeah, it's in the matrix. So you're going to be blowing out a lot of, you're going to make a lot of ATP. It's going to just replace.

In the normal cell, you're making most of the ATP from oxidative phosphorylation. But in the cancer cell, you're making most of it from substrate level phosphorylation inside the same organelle. Why don't our cells do this under demand? So if we jumped up and down and did 25 burpees right now, we would very quickly exceed our oxidative capacity for respiration, and we'd start making a bunch of lactate. Why aren't we also undergoing SLP? Well, we do. In the heart muscles, they do. On various cardiac restrictions and things like that,

a lot of this has been worked out in the heart. So it does happen. I mean, we do do substrate level phosphorylation, but it only can be done for short periods of time. It can't be done extensively. You can't replace oxidative phosphorylation. But it only can be done for short periods of time. It can't be done extensively. You can't replace oxidative phosphorylation under normal conditions with substrate-level phosphorylation. You hold your breath, you're going to be able to survive for a certain period of time. Lactic acid builds up. I mean, this was shown by Hoshkotchka when he did some incredibly interesting experiments

trying to hold various aquatic animals underwater and looking at the metabolic changes that occurred. So seals, porpoises, turtles, these kinds of things, he strapped them to a board, held them underwater, and then he would measure all these metabolites in the bloodstream. Now, these were animals that actually could live underwater. If they did it to us, we'd all be dead, right? We couldn't live that long, but five minutes at the most. But these animals could live 10, 15, 20 minutes being held underwater. And they weren't breathing. Of course, now they were stressed out because they were strapped to a board.

But the bottom line is you started measuring all these metabolites in the bloodstream. Lactic acid goes right through the massive amount. I expect that, right? And succinic acid. Succinic acid is another. So succinic acid is part of the, in the TCA cycle, is a powerful stimulatory towards oxidative phosphorylation. And it was being dumped out into the circulation. So it wasn't being oxidized.

So he claimed that it was amino acid fermentation that was doing this. So the body was grabbing amino acids and metabolizing them and generating energy through substrate-level phosphorylation. Well, it turns out the cancer cell is doing this in a massive amount because they don't have the oxphos. So you look at cancer cells and they're dumping out succinic acid. And succinic acid, it stabilizes HIF-1-alpha so you can continue the transcription factors for drive and fermentation. So this whole thing is just a massive shift from oxfos to substrate level phosphorylation. Does creatine phosphate fit into that SLP pathway or is that totally separate? I'm not sure about that. It could be a source of the phosphate groups,

but I haven't looked into that. Dominic may know a lot more about that than I do. So when you go back to sort of, there's an undercurrent here to what we're talking about, which is the view that you hold is the minority view today. It sounds like. Just it's only it's just a matter of time. Okay. Why do you think that is? What do you think is the I mean, I know people want to come up with conspiracy theories.

And that's sort of one of the things about social media that I find frustrating is people always want a conspiracy theory to be the explanation like, oh, the drug companies don't want this to be true or something. I find those things hard to believe. Do you think there's a better explanation for why these hypotheses are not being investigated with the rigor that maybe they should be? Well, you have to look at the discipline of the individuals that are working on the project. Okay. So if most of the people doing cancer research are molecular biologists, which they are, you have that perspective on the nature of the problem. So you don't look at respiration directly. You look at gene expression profiles that may be directly or indirectly related to that. And then you make claims about what's going on. So if most of the people are of a discipline that says that genes are changed and not looking at the actual consumption of oxygen and production of lactic acid, not looking at what Warburg actually looked at, then you have a very different explanation for what's happening.

So a lot of people today use the seahorse instrument to measure oxygen consumption. And when you put cancer cells and tumor cells, normal cells into a dish, they're all taking up oxygen similarly. And therefore, Warburg must be wrong. Warburg also said that tumor cells and normal cells, some will take up oxygen at the same rate, except the tumor cell is uncoupled and the normal cell is not uncoupled, which means that the oxygen uptake in the tumor cell is not linked directly to ATP production. People ignore that. So they just don't. And some of the most beautiful experiments- How would one measure that? ATP is very tricky to measure, ATP production. No, ATP can be measured. The problem is, is that what's the origin of it?

Well, that's what I mean. Isolating. So let's say you have a tumor cell and a non-tumor cell, and they're both taking up lots of oxygen as measured by calorimetry, and one's producing a bunch of lactate. But how can you tell if the cancer cell is taking up oxygen and not making ATP? Well, if it's taking up oxygen, well, if it doesn't make ATP, it's dead. All right. Sorry. If it's not making ATP commensurate with its oxygen consumption. Well, sometimes you look at that and you'd say, well, look at the oxygen consumption. The ATP production is commensurate with oxygen uptake.

Yes. Okay. That would be coupled, wouldn't it? As long as it's not producing lactic acid or succinic acid. Okay. So I'm a bit confused. Why couldn't it do both? Couldn't a cell undergo anaerobic metabolism, make ATP that is accounted for by the amount of lactate that's produced, but similarly take up oxygen and in a coupled fashion make ATP there? That's an important point because a lot of people stumble on that. The problem with that is that

when you're looking at the ATP production coming out of the mitochondria, it's not always easy to know whether it's from a coupled, generated by a coupled mechanism where the oxygen is in fact linked to the ATP through F1, F0 ATPase, or whether it's coming from mitochondrial substrate level phosphorylation. Ah, got it. So you can't, it's not easy to do the mass balance of this many moles of oxygen were produced or consumed and this many moles of ATP were produced. You can't do that math. Well, Warburg did that, but he was looking at- But he didn't know about SLP,

right? Well, lactic acid production, the production of ATP at the pyruvate kinase is substrate level phosphorylation, but it's cytoplasmic. Yes, yes. It's not mitochondrial. He did not know. He couldn't have known because the very systems that were, they didn't come out until the 50s, 60s, that we knew that there was another form of ATP production inside the mitochondria. What people have failed to realize is that they consider, every biochemical textbook

says we only get 2% oxygen coming out of the mitochondria through a substrate level phosphorylation, just like we get from the cytoplasm. But for cancer cells, people say, oh, we can get a lot more ATP from the cytoplasm, but not thinking you can upregulate the same phenomenon inside the mitochondria. As a matter of fact, we think that substrate-level phosphorylation in the mitochondria is far greater than the amount of ATP produced in the cytoplasm. And that's because others, Cantley and others, a number of people have found that the PKM2 isoform of pyruvate kinase doesn't make much ATP. It makes a buttload of lactic acid, but it's not linked to the ATP production.

So therefore, they have to say respiration is normal because the cell is making so much ATP. But if Otto Warburg is correct and all of the structural biochemistry is correct, the mitochondria can't be making oxygen from oxidative phos. It can't be making ATP from oxphos. It can't be because the structure of the organelle is defective. So where the hell is all that damn ATP coming from inside that organelle? And then when you look at the data that we have, and glutamine is being consumed in massive amounts, so it's got to be coming from substrate level phosphorylation. What is the fundamental structural defect in the mitochondria? Which is interesting. I'd never thought until this discussion about the

possibility that you could have a completely normal mitochondrial genome and just have structural defects. And then of course, obviously you can have genetic abnormalities that lead to protein productions that create structural problems. But in the case of the former, perfectly normal genome- Mitochondrial DNA genome. That's right, mitochondrial. But you now have a defective. What is the actual physical defect? In the structure, the number structure, this is the, it can happen in many different ways. For example, if a carcinogen enters into the mitochondria,

they cause a lot of oxidative stress. And what we found in our massive studies, this is how we got onto the mitochondria, knowing that Otto Warburg was in fact correct. I mean, at first I didn't know what the hell was going on like everybody else. But when we found no mutations in the mitochondrial DNA and we knew these cells were fermenting because they were making a lot of lactic acid,

then we started looking at the lipids inside the mitochondrial lipidome. We call it the lipidome. And we have found that cardiolipin, the signature lipid in the inner membrane, is defective in all the tumor cells that we've ever looked at. So that tells us right there that there's a problem in the function. And then we link that to abnormalities in OXFOS. So clearly, lipids are abnormal.

That would affect the function of the proteins of the electron transport chain. Therefore, you're not going to generate the amount of ATP through oxidative phosphorylation because the very lipid and protein structures are abnormal. And you can't produce the amount of ATP. So that supports Warburg knew that there were many problems in the mitochondrial function that would then force the cell into fermentation. So what did they ferment? They ferment lactic acid and succinic acid.

What are the fuels for that? It's glucose and glutamine. So glucose and glutamine are ultimately the fuels that drive the cancer. And they drive it through a process of substrate level phosphorylation occurring in the cytoplasm where they can build a lot of metabolites for growth and also through the pathway called glutaminolysis. Now, one can't render glucose zero, meaning there's no dietary or pharmacologic intervention that could reduce glucose levels to zero. Are there any that could do that with glutamine? Or is it similar? Let me address the glucose issue. We can't get to zero. Are there any that could do that with glutamine? Or is it similar?

Let me address the glucose issue. We can't get to zero, but we can get damn close to it. All right? So we have people, published papers, people who have gone powerful, therapeutic fasting only, and then given large injections of insulin. Sure. And they've got to below one millimolar. Yeah, 0.5. But sustainably, it's very difficult to be below about three millimolar, right? Right, right. But here's the situation.

The problem is, is when you do that, you go into calorie restriction, restricted ketogenic diets, you already are lowering the blood sugar to a significant degree. And what we found is that glucose transporters actually get upregulated in the normal cells when you start doing this. So the normal cells become glucose hungry. And they become direct competitors now with the tumor cell that absolutely needs the glucose because the normal cells can burn the ketones and stay alive. The tumor cells can't burn the ketones because they're mitochondria defective.

So you need a good mitochondrial system to burn ketones for energy. So what we do by calorie restriction and keep restricted ketogenic diets is we make the normal cells glucose hungry and we transition them over to ketones, keep them alive, but they're still glucose hungry. And they are now competing directly with the tumor cells that absolutely have to have the glucose. It's interesting because clinically we don't see that, right? So clinically when we put most people on a ketogenic diet or a calorie restricted diet, in the short run, they actually become physiologically quite insulin resistant. Meaning when you challenge them with glucose, they have a paradoxical rise in glucose and insulin that's overcome

by refeeding them with carbohydrates for three or four days prior to the glucose challenge. And the offered explanation is that during a period of starvation and or carbohydrate restriction, the muscles, which are obviously the dominant sink for glucose, basically become resistant to insulin, not in a pathologic way, but rather in a way to allow the brain to have access for the remaining glucose. Well, if you do it in acute systems like that, rather than the chronic changes that we talk about, you can get those kinds of an effect. Generally, calorie restriction

makes the body super insulin sensitive. Yeah, it's interesting. This is something I've struggled with because I was on a ketogenic diet for three years. And at the end of that period of time, I went up to Stanford and did an insulin suppression test, which is along with the euglycemic clamp, really the gold standard for measuring insulin sensitivity with Gerald Riven, the late Gerald Riven. And Jerry was just interested in my physiology. It

was like, wow, you're kind of a weird guy. You're on this bizarre ketogenic diet, hadn't studied it. He did at the time have a publication of about 400 non-diabetic subjects who he had put through the insulin suppression test. The way this test works for the listener is you take an individual, you hook them up to two intravenous lines, one that puts glucose in, one that puts insulin in. And over a six-hour period of time, you follow a protocol of injecting glucose and insulin. And after about six hours, the glucose level reaches a steady-state level referred to as the SSP or steady-state plasma glucose level. And the higher that is, the more insulin resistant you are said to be, the worse you are at glucose disposal. The lower that is, the more efficient you are able to dispose of glucose. And that number, the SSPG, correlates to the one over the M value,

which is the Y-axis intercept on the euglycemic clamp. So anyway, so I went to Stanford one day. Well, let me, why would you inject glucose and insulin? If you were on a ketogenic diet, you'd be already, and you were to take glucose, your insulin levels would already go up to the maximum physiological. So you're actually giving too much insulin in a situation like that. Well, so this was part of the issue, right? We didn't know what to do because the protocol is all developed around people not on a ketogenic diet. These are all people eating a standard diet. But what you're alluding to is what we discovered very quickly. So again, this is supposed to be a six hour test. And when you looked at, and I looked

at the data before we did this to get a sense of what the parameters were of the 400 non-diabetics that they had done this on the most insulin sensitive person ended up having an SSPG of about 79 milligrams per deciliter, meaning the lowest that anyone's glucose got following this protocol was 79 milligrams per deciliter, which is perfectly reasonable. And the highest was, I don't recall this, but we could look up the paper, but I think it was somewhere in the vicinity of 200, 300 milligrams per deciliter. So that's a person who is functionally a diabetic. And even though they're quote unquote, you know, normal, their A1C was less than 6.5,

they're very soon to be a diabetic. And of course, when you do this on people with type two diabetes, they're all very, very high. So we're doing this test where they're sampling glucose levels every 30 minutes. And within an hour, meaning after just the first, second, third sample, it was clear my glucose was going down very quickly. So they said, okay, we're going to back off on the insulin to your point. At 90 minutes, and I have to go back and look because I have all the data. I could be wrong. Maybe it was a little longer than that. I think it was about 90 minutes. They basically turned the insulin off. Now at this point, my ketones started to go down. I think between the

90 minute and the two hour mark, it got really bad, really quick. And my ketones at this point had gone from, I don't remember, somewhere between two and a half, maybe three millimolar down to less than one millimolar. And they said, you know, we're going to stop the test now because your glucose is in the 40s. I believe I was at about 48. Yeah, no ketones. we're going to stop the test now because your glucose is in the 40s. I believe I was at about 48. Yeah, no ketones. You're going to go unconscious. You got to be careful.

Yeah. So in the end, I almost did go unconscious. And the last thing I sort of remember was the profound perspiration that came over me, which is very different from the perspiration you experience on a day like today in Boston where it's hot and you're sweaty. It's not that type of a perspiration at all. It felt like I was in a shower and I began shaking and probably was about to have a seizure. And then they went, so the last blood glucose I think they got on me was about 31 milligrams per deciliter. And when they were injecting the dextrose, the D50, I was conscious enough to

realize the IV had infiltrated. So all I felt was the most ridiculous burning sensation in my antecubital fossa because I realized the dextrose was not getting into my- Why you put yourself in this situation? I'm an idiot. I mean- The worst part of that story is I would never do any of that stuff. I would never do any of that stuff. When I came back to life, I had a huge, huge infiltrated IV in my right, in my left antecube. I took a picture of it and I sent it to my wife and who I didn't even tell that I had flown up to San Francisco that day.

I think I was just like, you know, I travel so much that like I could be gone for a day. She wouldn't even know it. And I was like, hey, check this out. And she's like, where are you? And I was like, oh, I'm up at Stanford today doing such and such. She's like, what, check this out. And she's like, where are you? And I was like, oh, I'm up at Stanford today doing such and such. She's like, what? You just about died? And like, you got to, if you're going to die, I mean, you're an idiot, but you got to tell me in advance where you're going to be when you die.

Yeah, well, I mean, our goal is not to try to kill ourselves. It's to kill the tumor cells and make the rest of us healthy. Okay, so my long-winded story there was to illustrate a point. I turn out to be an exception to that rule. So, and I did this with oral glucose tolerance tests as well. And I never had that physiologic insulin resistance. In other words, I seem to be one of the people for whom what you're saying seems to be correct chronically, which is whenever I'm on a ketogenic diet, my glucose disposal is remarkable. But now putting on my sort of-

Your insulin, you're very high insulin sensitive. My muscles become very insulin sensitive, but without the refeeding of carb. Yeah. Yes. What I noticed though is clinically, I see so many patients for whom that is not the case. If I do an OGTT, an oral glucose tolerance test on a patient in a ketogenic diet, I feel like, and again, I think other physicians listening to this will have to weigh in with their opinions. I feel like 70% of them fail the OGTTs and look like they have diabetes or are very soon to. However, if on the repeat OGTT,

you just say, look, for the three days prior to the test, you're going to eat two potatoes a day, they pass with flying colors. In other words, they show that they are indeed very insulin sensitive, but they need to be primed a little bit. So my point though is if that's the case, if the 70% of patients or whatever the number is, they wouldn't actually benefit from this effect, because they'd be walking around and the muscles you know, they'd be, the muscles would be selectively not consuming that glucose. Unless you can get the blood sugar down. Like, as I said, we're, we're experimenting now because don't forget our goal is to starve the tumor cells. This, I mean, we're singularly focused on this. The issue here is how you starve the fermentable

fuels without causing- Without starving the normal cell. Yeah. And, or harming at all. It sounds to me like you were brutalized in that experiment. Well, yeah, yeah, yeah. That's a not to be done at home. That's not what our goal is here. Our goal is to emerge from the therapy healthier than when you started. So the question becomes, how low can you get blood sugar without compromising

the health status of the individual? And again, if you're in ketosis, you can push your blood sugars down really low. But you'd want to do this without insulin because insulin itself is pro-tumorgenic. Only if the blood sugars are high enough. Once you get those blood sugars down and you take away all the glucose from the body or the majority of it, it kills the tumor cells. We have the data to support that. Insulin per se is killing the tumor cell? Insulin, no, no, no. Or the reduction of glucose? The reduction of glucose.

So you're saying basically- Because you can't eat insulin. Insulin doesn't give you ATP. But you're saying insulin does not function as a growth signal outside of its anabolic activity and taking up glucose? Well, if you have insulin-like growth factor, of course, is linked to the insulin, of course, that facilitates the uptake of glucose. I mean, if you don't have glucose, what else is going on? Because without ATP, you can't get energy anyway. So the goal is to deplete the sources of fuel to the cells.

So insulin, you can't eat insulin. Now, insulin drives the pyruvate dehydrogenase complex, which facilitates. That's why they say, oh, you can get this and that. That's only if you have a lot of glucose around. Insulin becomes pro-tumorigenic. But if you have very little glucose and you give more insulin, remove the glucose. It doesn't stimulate tumor growth. We have direct evidence to support that.

So, in fact, the Germans used to do that. They used to put people into insulin comas. The problem is you don't want anybody going to an insulin coma. If they were in ketosis, you could give a shitload of insulin and you're not going to die. We have evidence in the literature to support that. So you got to keep the door shut on that insulin, on the glucose as tight as you can without harming the rest of the body. So we use insulin and then we do hyperbaric chambers, but that comes only after you shut the door on the insulin and the glutamine. So if you- So how do you shut the door on the insulin and the glutamine.

So how do you shut the door on glutamine? The glutamine door, you have to use drugs. And the best drug we found so far is Don6-diazolucine. It's an old drug. It was made years ago. They used to use it on cancer patients, but they never targeted glucose at the same time, so the tumor cells were sucking down the glucose. As a matter of fact, you can even make them more glucose sensitive if you take away the gluten. So there's no dietary strategy that could effectively reduce glutamine. No. Glutamine is a non-essential amino acid. We can make glutamine from glucose. I mean,

so it's why it's called non-essential. However, in physiology terms, it is essential. It plays a massive role in the gut, in the immune system, in the urea cycle. I mean, it's such an important amino acid and it's ubiquitous. It's the most abundant amino acid in our body. Yeah, that's a funny distinction. I'm glad you pointed that out for this is a total aside, but I'm sure that there are people listening to this who get confused by the term essential and non-essential because it's eight of them are essential and 12 are non-essential or something to that effect. But what you're pointing out is an important distinction. They're non-essential because we don't have to get them exogenously.

They're still essential for our survival once produced endogenously. Yes, absolutely. And glutamine, if you look, it's the most abundant amino acid in our serum. It's everywhere. And our immune system. And the point being, there's nothing you're going to eat or not eat that's going to change that. And people ask me that all the time. It's got to be drug.

You got to do it drugged. And you have to use drugs, but it has to be done strategically. And you have to have people that are knowledgeable about this. You can't just have some guy just jack you up with a drug that blocks glutamine. Because it has to be because your immune systems will be compromised. And our immune system is needed for the health of our gut, the health of killing bacteria. And if you paralyze them too much, then you're going to get infections. You're going to have all kinds of other issues.

So that's why we developed the press pulse concept. So you press the glucose hard with diets and drugs, and then you pulse the glutamine. So what we think is going to happen is we will target the glutamine with a drug that will selectively kill tumor cells, paralyze the immune system, but then immediately give large amounts of glutamine back. And the issue, of course, is that you're going to restore your gut, you're going to restore your immune system because they're only paralyzed, they're not killed. And when you say immune system, are you referring to the cellular or humoral system? The cellular, mostly. Because you've implicated, we're going to come back to it, but you've kind of implicated the humoral system with the macrophage in terms of

mutagenesis. Well, we're talking about the cellular immune system. Yeah, you're talking about the T cells. And B cells and macrophages and natural killer cells, leukocytes, all these kinds of things. They're all glutamine dependent. They're all heavily glutamine dependent. Okay. So if you have a patient that's burned the skin, now you've opened up the bacteria, you have to give large amounts of glutamine because the immune system is needed to kill the bacteria. You have to restore the gut function. A lot of the cells in the gut are glutamine dependent. So that's why you give large amounts of glutamine to cancer patients that have been subjected.

But the problem is, of course, is the tumor cells are using the same fuel. So you have to know. And as I said, if you kill too many of the tumor cells too quickly, you've got to have a cell system to remove the corpses. You've got to have some. And that's what the macrophages do and some of these other immune cells. They'll come in and remove the corpses, the dead cells. Otherwise, you get infections. You die from the indirect effects of these other immune cells. They'll come in and remove the dead cells. Otherwise, you get infections. You die from the indirect effects of these things. So you have to know how to strategically target glutamine without compromising the normal physiological systems

that we have. So before we get into the therapeutic stuff, which I understand is probably what everybody wants to hear about, I still want to get back to kind of understanding some of this stuff a little bit better. So experimentally, I'm still struggling with this sort of chasm in belief systems between what sounds like the majority of people who take the view that says, look, the respiratory system of the cancer cell is relatively normal. If you're seeing an increase in fermentation, it's an artifact of a higher throughput of substrate to generate more building blocks. This strikes me as a very testable hypothesis. This really shouldn't be, we shouldn't be debating this. There should be a set of experiments that could resolve that, correct?

Yeah, and I think that diagram there on the board is the illustration of the strategy to test that hypothesis, basically, which is where are they getting their energy from? The bottom line is where are they getting their energy from? If you stop their energy. The board picture, by the way, we're looking at everything. We're looking at the, we'll put a picture of this, of course, up there, but it's basically the TCA along with everything outside of the TCA as well. It's effectively looking like it's even metabolic pathways that I can't name at this moment.

Yeah, because you have to try to integrate, like you said, you have to try to integrate all of the knowledge that we have on the biochemical systems into a strategy to manage the disease. And I break it down into more simplistic things. In other words, energy. Without energy, nothing grows. And the evidence that I'm convinced about, that I've read massive amounts of literature and looked carefully at everything, the structure and function of the mitochondria in tumor cells is compromised. All right. That's a fact. In my mind, that is a solid fact. And to deny that, one would have to ignore the evidence that I've looked at. You have to look at a mitochondria and say, no, that mitochondria that has no cristae and is very few in number,

there's nothing wrong with it. Okay, let's call it white-black and black-white. But let's go one step further because there's an objective way to assess structure, but shouldn't we just ask the functional question? Experimentally, I mean. Yeah, of course. And we do that. So we know structure dictates function. That's common in biology. Then if that structure looks abnormal at the electron microscopy level, at the various levels, why don't we look now at the activity of the proteins in the electron transport chain? And just as this may be a naive question, but there can be large ranges of structure that could still produce optimal function. And you

would think that for something as important as respiration, which to your point might be the single most important function of a cell as evidenced by the fact that toxins like cyanide are uniformly fatal within seconds, you'd think that the structural leeway within a mitochondria would be so high that you could, let's just say you could quantify structure as a scale from one to 10. And obviously a 10 out of 10 structure is perfectly functional. You'd want to believe that that thing would function good enough down to like a two out of 10. And only if you were staggeringly compromised does everything go to hell. So in other words,

just to push back for a moment, one could argue, hey, yeah, of course there's structural changes, but they're not functionally relevant because they're within a parameter space. Yeah. No, that's an important point. And I think the normal flexibility of ourselves- Yeah, that's the better word. It's the flexibility. Yeah. The normal flexibility is able to accommodate those kinds of changes over the short period of time. Mitochondria is such an incredibly vibrant system. It's a living organelle inside of our cells, right? It's a separate organism, actually. Separate DNA.

Yeah. And they've turned over all of their DNA to the nucleus, except for 13 critical genes. And those 13 critical genes control the life of the cell. Why should I do this activity when I can get a dumbass nucleus to do it for me? But I'm still going to hold the keys to the kingdom. There's still 13 genes that if anything goes wrong with them, you're dead. And this is the whole thing. Why cancer cells don't die through the apoptotic mechanism?

Because the very organelle that controls the kill switch, the switch doesn't work. So the cell bypasses the normal control of life apoptosis in the cell because the very organelle that dictates that is now defective. So consequently, this cell now is reverting back to the way it existed before oxygen came into the atmosphere on the planet. They were all fermenters. They grew with unbridled proliferation until the fermentable fuel in the environment disappeared They were all fermenters. They grew with unbridled proliferation until the fermentable fuel in the environment disappeared and they all died. So it was very clear what was going on before oxygen came onto the, into the atmosphere. Cells would proliferate unbridled. There's St. George, Albert St. George, he was alpha period in the existence of the planet.

So everything was working on substrate level phosphorylation. It was no oxidative phosphorylation. They're all doing that. What we have in our system today is these same capabilities, but we don't use them, but only for very short periods of time under very various physiological stress situations. They don't become permanent. In the cancer cell, they have become adapted because as Warburg said, you can't get a cancer cell from a cell that cannot ferment. So neurons in the brain can't ferment for very long. You rarely, if ever, get a tumor out of a neuron, except neuroblastoma, which is outside the brain. So heart, cardiac,

myocytes rarely form cancers. Even muscle cells rarely form because you have the sheets and stuff. So cells that need a lot of oxidative phosphorylation rarely can form a tumor. Only tumors can form in those cells that can upregulate fermentation pathways. If you can't do that, you're going to die. But wait, wouldn't skeletal muscle be one of the highest candidates to be able to upregulate fermentation given their ATP demand? Yes, but they have a syncytium of mitochondria inside the muscles and they've adapted. This is their part of the normal physiology. They can ferment for periods of time under extreme stressful conditions. They can't permanently do that. They die. The muscles will die on you. The cells will die if you try to force them into a

long-term fermentation metabolism. But they have the capacity to upbreak fermentation for short periods of time, like many cells do. But brain can't do that. Heart can't. You're going to have a heart attack. Let's go back to the, this is an interesting point you bring up. Let's go back to a myocyte within my quadricep versus a epithelial cell in my colon. Yeah. To your point, the probability I will get a cancer that comes from the myocyte in my quadricep is virtually zero. No, it doesn't say virtually zero.

But it's, I mean, outside of a sarcoma. Sarcoma is, well, you know, what is a sarcoma? What's the origin of the sarcoma? What kind of cell? Depends. It can be a myoliocercoma. There can be many. But just humor me for a moment.

Probability-wise, the myocyte in my quadricep or my pecs or something forming cancer is so much lower than the epithelial cell in my colon, right? Yeah. Or an epithelial cell in your kidney or your bladder or one of these kinds of things. I just pick colon because it's such a high cancer probability. Right, right, sure. Breast is another one. Yeah, yeah, right. So what is it, explain to me again the difference in their, because I would say like the muscle cell is far more adaptable at making lactate when it needs to, because it's, I demand of it much more than I demand of my colonic epithelial cell. But then say what you were saying again about the toxicity of lactate to that cell versus the epithelial cell in my colon.

Well, the epithelial cell in your colon, if it becomes, and again, it's a longer process. It's not something, you don't go from a normal cell to a cancer cell overnight in a colon. There are some situations where cancer can happen much quicker than people would normally think. But in general, it's like it's a protracted process. So the cell has to have the capacity to shift from an oxidative process to a fermentation process. You have to have the machinery in the cell to be a fermenter

because without that capacity, you can never become a tumor cell because the cancer is twofold process. One is the gradual chronic interruption in respiratory function coupled with a gradual compensatory shift to the alternative form of energy, which is substrate-level phosphorylation. So if the cell is incapable of making that shift, it will never become a cancer cell. It can't because in order to be a cancer cell, you have to be able to replace oxfos with fermentation. And if you can't do that, you're not going to become a cancer cell. And that's why brain neurons rarely become tumor cells because they can't do that. Brain cells die. So if you interrupt oxidative phosphorylation in the neurons of our brain, we call that neurodegeneration.

So we don't generally get tumors. We get tumors from the glial cells and the microglia and these kinds of things. Yeah, this is important. I mean, I know what you're saying, but I know the listener will be confused by this because they're going to say, but gosh, my aunt had brain cancer. It's very important that we distinguish between the glial cells and the neurons. Right, and the microglia, there's another form of which we think are neoplastic. But when we hear about astrocytomas, which would be the most common brain tumors, they're not actually, the cancer is not existing in the neuron.

That's correct. Yeah. They're not neuro. So these are the kinds, or cardiomyocytes. Yes. You generally, because you're going to, you know, they just, they die. These, because they're packed with mitochondria. You start, they start fermenting.

You can't, they die. They can't deal with that. Again, see, that's the part, Tom, that just confuses me. It's so counterintuitive. I would think that if there's going to be a cell in my body that I want to be able to buffer lactate and specifically buffer the hydrogen ion that comes with it, that's actually what's killing the cell. I would want my cardiac myocyte to be the single most robust cell in the body because it has to be the last guy standing. Yeah. Well,

you know, this is the whole thing. When you get a, when you get a heart attack, you die from brain damage. You don't die from your liver and kidneys are fine. That's why you can donate your liver and kidneys when you have a heart attack, because those cells are not dying because they have the brain is most susceptible to the hypoxia. But the point is, even at the level of the highest stress, I would want my cardiac myocytes to be able to access all fuels, glucose, fatty acid, ketone, you name it. They do that with heart degenerative heart disease, but they don't form cancer. They have a capacity.

And this is where we found a lot of substrate level phosphorylation in the mitochondria, the TCA cycle, was discovered in stressed hearts. Okay. So because they were saying, well, the heart should be dead, right? I mean, why is it still functioning here? Where's the ATP coming from? And they found that most of the energy in the heart is coming from mitochondrial substrate level for shorter periods of time. I'm not saying you can't do this as a permanent shift, but the concepts were developed from the work in the heart. But you would expect, yeah. Well,

same with my brain. I mean, if you're brain damaged, you can't function either. I mean, so the two organs, heart and brain, are remarkably dependent on oxidative phosphorylation for function. And disruptions of oxidative phosphorylation are usually catastrophic for those cells. I mean, of course, after a time. I think I understand your argument. I was thinking about it in reverse. You're saying because the brain and the cardiac myocyte have evolved to be so efficient under oxidative conditions, it's not so much that lactate is

harmful to them. It's that once you start to disrupt, if the hypothesis is correct, that it's the disruption in the mitochondria and its capacity to carry out oxfos that's harmful, you die long before you bother getting cancer. Those cells undergo apoptosis or just die. I understand your point. Yes, that's the point. That's the point. So the key is that how long does it take to transition a cell from an oxidative phosphorylated state in a cell that can become a tumor like a colon, as you mentioned?

So the real problem that these other cells have where cancer is so ubiquitous, whether it be breast or colon, according to this hypothesis, would be their metabolic flexibility. It's their capacity to easily wax and wane between, I shouldn't say, it's not their flexibility, it's their lack of dependency on oxidative phosphorylation. Well, they depend, I mean, obviously, like you said, with cyanide, I mean, it shuts down, everything's dead real quick. But that happens so quickly that they don't have the ebb and flow. It's their capacity to upregulate fermentation over time because it doesn't happen overnight. It's a very gradual thing. And heart cardiomyocytes and neurons of the brain can't do that, that these other cells are capable of doing. And as I said, what happens is the, again,

you had that mitochondrial stress response. And this is where your oncogenes come in now. Because the oncogenes are transcription factors that upregulate fermentation pathways. So basically, when you damage the respiratory system of a cell, HIF-1-alpha becomes stabilized. And now you can upregulate glucose transporters into the cell. MYC is a glutamine. They all overlap each other. Lactic acid dehydrogenase.

All these enzymes that are geared for maintaining a fermentation metabolism. The transcription factors that make those pathways upregulated are the oncogenes, basically. So the oncogenes have to facilitate. If you're not going to get the same level of energy out of your oxfos, you've got to compensate to get, because as I tell everybody, the singular most largest consumer of energy in any cell is the pumps. These pumps that are on the surface of the cells that maintain the ionic gradients that allow what we call life. Because once you reach equilibrium, you're dead. So most of the energy in any cell, cancer cell, heart cell, and it's the proton motive gradient

across the membrane that determines whether or not that cell is going to be alive or not. So you need ATP for that. If the ATP dissipates, you just swell and die. You get apoptosis or whatever. So you have to then determine, where's my ATP coming from? How am I going to keep those pumps going? So, and if fermentation becomes a replacement, therefore I'm going to need a lot of extra fermentable fuels to make up the loss of the energy that I'm getting out of oxfos. So oncogenes have to turn on because they are the transcription factors that upregulate the transporters for glucose and glutamine. So you're bringing in two alternative fuels to make up the

difference. And therefore, the genetic behavior of the cell begins to change. And then because the cell is now using damaged respiration, you throw out a lot of reactive oxygen species from the damaged respiratory system. And they cause, they're mutagenic and carcinogenic. So the nuclear genome gradually collects all these different mutations and defects coming from the ROS of the mitochondria. But at the same time, the cell is not dying from this ROS because it's being protected by the fermentation pathways of glucose and glutamine. How much of that lactate is leaving the cell and going back to the liver to undergo the Cori cycle? Yes, a lot of it. A lot of it does. Has anyone ever looked at patients who have a very, very high tumor burden and seen if they appreciably have

higher serum lactate levels? Yes. And blood cancers have been done. In fact, there have been some patients who have had various leukemias where they died of lactic acidosis from so much lactic acid being produced from the tumor cells. There's a couple of papers reported on that. Lactic acidosis from massive leukemias. So the leukemia, the same thing, it's a blood cell. They're mitochondria defective, so they're thrown out a lot of lactic acid. Although that's a confusing one because I could come up with another explanation, which is in very, very severe leukemias, you could also create multiple end organ ischemia just due to the defective nature of the white blood cells could actually cause capillary damage.

And that lactic acidosis could actually be from other organs. That's true. And the paper that I read seemed to focus on the lactic acidosis from the cancer cells themselves. But it doesn't rule out what you just said. Yeah. And I don't know how you'd quantify the distinction. It's another one of these things. But the question is, but you're right. You can't, like a solid tumor, seeing a lot of lactic acid in the bloodstream, the core recycle clears it out pretty quick. So you're going to be taking that lactic acid and making glucose again from it, which then goes back to the tumor.

Do tumor cells upregulate the machinery? I believe MCT2 is the lactate transporter. Do they upregulate that specifically? Yeah. I mean, it's upregulated and so is lactic acid LDHA, lactic acid dehydrogenase A, which converts pyruvate to lactic acid rather than B. See, most cancer cells do not have elevated levels. This is why some people say, oh, cancer cells can to lactic acid. Oh, yeah. Rather than B. See, most cancer cells do not have elevated levels. This is why some people say, oh, cancer cells can burn lactic acid. Oh, where are they burning it? Oh, well, because they're taking it back in.

The cancer cells are burned. No, that's bullshit. If it can't put pyruvate into the mitochondria, it's pumping lactic acid. How is it possible we take lactic acid and make it back to pyruvate and put it in there? If it does that, and it's going to go up to,

you're going to store it as glycogen. It's not going to be respired. But do you know if anybody's looked at that and seen if MCT2, I think it's MCT2 is the transporter. Yeah, they're upregulated. It should be upregulated a lot. Yeah, they're upregulated. There's no question they're upregulated. Because otherwise the hydrogen ion would poison the cell.

Yeah. So you have the whole thing is upregulated, monocarboxylic acid transporters. They dump out, and they also take in ketones. Don't forget that same transporter brings in ketones. So when you go into ketogenic diets, the MCTs are upregulated as well. So you're bringing in more ketone bodies now to replace those. There's an irony for you, right? The thing that you use to bring in ketones is giving you the exit for lactate, which protects the cell from the harm of the acidosis that comes with the hydrogen ion. In the micro environment of the

tumor, it's a real mess. So some of the lactic acid is persisting, the hydrogen ions are persisting until they can ooze out into the local bloodstream and get back to the liver that way. But otherwise, it's going to be a real acidic mess, which then contributes further to the fermentation behavior of the cells, which then they're resistant. So they're fermenting, right? So they don't need blood vessels. So this is the whole why the anti-angiogenic field has failed, because they said, well, we'll target the blood vessels, and therefore the cells will die because they can't get the oxygen and whatever. But the cancer cell doesn't need that. I mean, it doesn't need the blood vessels. It can ferment. Did you know Judah Folkman, by the way? You guys were basically

neighbors. Yeah, yeah. I know he came down here, gave a talk. He targeted some unusual kinds of cancers with his anti-angiogenic. But Napoleon Farrar, I believe, was the guy who started taking that all off. And he even came to a meeting and said, none of this stuff is working. Well, because the, and this is why Avastin, as I wrote, you know, avoid it like the plague. It's a stupid drug. It was taken off the market for breast cancer because it was harming more people than it was helping. But they still use it for brain cancer.

And I think it makes people- Do they still use it for colon cancer as well? I don't know of colon cancer, but certainly for brain cancer. So what are you doing? You're targeting the blood vessels and then forcing these cells to spread throughout your whole brain. So just for the listener, right, Avastin is an anti-angiogenic drug. This was a Genentech blockbuster, right? Yeah, Bevacizumab is the name of the drug.

Yeah, and they still use it. I think it's despicable to consider anybody using it. I mean, don't they know the biology of the problem? They would never do that. And it's already been a bust in all the brain cancer studies that I've seen. In fact, my friends have told me that work on this. But it makes the aim-

It's generally been priced out of use. Certainly outside of the US, I don't think any third-party payers would cover it. And it's a very expensive drug. It's about $100,000 a year drug. Yeah, and all it does is contribute to the invasive behavior of your tumor cells. And all of these other things.

You're basically driving this idea, which I haven't wrapped my head around yet, is you're actually enhancing the promotion of the hypoxic factors that are giving cancer some of its selective benefit. Yeah. And don't forget the cells that are invading, which are coming from disrupted microglia in the brain, macrophages. They'll invade. They already have the capacity to do this.

They live without blood vessels. So you're facilitating the invasive behavior. And this has been seen on histological preparations, like brains that have been looked at after Avastin. They find tumor cells spread through everywhere in the brain. Rather than clustered in one area, it's like they've just gone everywhere. But when you look at the image, the radiographic images, it looks good because you don't see the necrotic area that you would

normally see. The image looks a little bit better. You tell the patient, it looks like it's working. But the overall survival is no different. Sometimes it's even less. So it's a false image of what's going on. You can't see the big central area. It looks like it's very vague and diffuse. And you look at the pale, yeah, it looks like this thing is working. Gives the guy false hope, you know, because the end result is look at the overall survival statistics and they're abysmal. So I want to go back to something you said a moment ago. You said macrophage, which reminded me of a point you brought up earlier, which I guess I'm just not really familiar with, which was the idea that the macrophage themselves may be responsible for actual metastatic behavior. Can you say a bit more about that?

Well, this is a concept that goes all the way back to Akhil from 1906 in Germany, where he was able to show that in colon, I believe it was colon or melanoma, I can't remember the tissue. He was actually observing fusion behavior between the neoplastic cells and the cells of our immune system. And then claimed that he thinks after this fusion event that these cells become much more aggressive and much more dispersive than before these fusion events. than before these fusion events. This was then solidified by the work of John Pawlik at Yale University, where he did some beautiful experiments showing that malignant melanoma is actually a macrophage disease. They're resulting of fusion hybridization.

This was then further established by Melissa Wong and her group at the Portland Medical Center there, the Health Science Center in Portland, Oregon. Beautiful work showing how, in the colon, how macrophages were fusing with neoplastic stem cells, forming these hybrid cells. So the question, and we know that all these metastatic cancers are highly fermentative. We know that's a fact. They're all highly fermentative. And they're all very, very invasive and they spread, they migrate through the blood-brain barrier. They migrate everywhere. They just invade. And these are all very, very invasive. And they spread. They migrate through the blood-brain barrier. They migrate everywhere. They just invade.

And these are all behaviors of macrophages. When you say fusion, so you have a neoplastic cell that is above the basement membrane. And you have a macrophage. And tell me what the fusion actually is. Are they fusing genetic material? Or are they just fusing cytoplasmic material? What's actually happening? Well, it's a combination of both, actually.

So macrophages, cells of our immune system, are extremely fusogenic. They do this to wound healing. Like you'll see multinucleated giant cells in a lot of parts of our bodies during wound healing and this kind of thing. And cancer cells, you also find a lot of these multinucleated kinds of cells. So our body recognizes wounding as an acute problem, and the immune system will come into that local area to facilitate wound healing. And when the wound persists, sometimes these cells will fuse with each other and fuse with other cells in the microenvironment to facilitate wound healing. The problem is, is if you have an epithelial cell,

like a breast cell or a colon cell, that is coming and becoming neoplastic, becoming dysmorphic in its growth regulatory, and it's fermenting, but it doesn't have the capacity to grow anywhere outside of that local area. It doesn't have the capacity. So our immune cells come into this lesion, if you will, that's persisting. The immune cell throws out growth factors and cytokines to facilitate the wound, to facilitate wound healing. The problem is those factors are also facilitating the growth of the neoplastic cell. So the neoplastic cell is dysregulated, but the very cell that's coming in to try to correct the wound is now provoking the cell to grow even more.

But what is the wound that the macrophage is coming in to see? Because the neoplastic cell has not yet violated the membrane beneath it. No, but it creates a, it throws out lactic acid and creates a kind of a hypoxic micro area. Okay. A micro area of hypoxia because the lactic acid is a signal of hypoxia. It's a signal of some sort of damage. You're not supposed to have pockets of built-up lactic acid in parts of your body. So it sends out, and normally if this does happen, if we have a contusion or a cut, cells of the monocytes mass migrate out of the bloodstream, go into the wound, clear up the debris, kill the bacteria, and then move out of that section,

go back to local lymph nodes and sit there in the event that they need it again. Or if they're pus, they form pus. They're all massive numbers of white dead blood cells. So these cells are part and parcel of the correction of the wound. The problem is if you have a colon lesion or a breast lesion from an occluded milk duck or whatever, or a lesion in the colon, you have a population of cells that will start to proliferate, creating a damage to the local microenvironment, signaling a system that's immune. There's something going on here.

Right. So when the monocyte gets out and differentiates, becomes the macrophage, goes to this now poorly differentiated cell, why doesn't it just kill that cell non-specifically, because this is just a macrophage, and how does that- Well, macrophages aren't it just kill that cell non-specifically because this is just a macrophage? And how does that- Well, macrophages aren't designed to kill cells. They're designed to kill bacteria that may be in the microenvironment. Don't forget they're a wound healing cell.

But going back to the bruise example, right? So you get a contusion in your thigh. The macrophage does play a role in clearing that cellular debris. Yes. So why doesn't it just effectively do the same thing with the cancer? Or with the soon cell or with the soon to be cancer cell? Yeah, because the cell is not recognized as being, it looks like it's a part of the local normal epithelial cells. It's not looking as if this is a foreign invader. This

cell has all of the, it looks like a regular epithelial cell that's proliferating. Because don't forget, we replace our cells by proliferation. But the lactate secretion, which is what got it there in the first place, wouldn't that tell the macrophage, hey, something's still wrong here? Yes. This cell is hardwired to do what it's supposed to do. It's not like thinking, oh, let me problem solve. It's not a problem solving cell. It's hardwired to respond to a particular environmental issue. I see. So you're saying the lactate is the fire alarm that got it there, but then when it gets there, it doesn't see the fire. No. Well, it tries to put out the fire, but the problem is the molecules that are used to put out

the fire are actually stimulating the growth of the cell that shouldn't be growing. So it's out of context. Okay. So how does this facilitate metastases rather than just local advancement? How does this facilitate metastases rather than just local advancement? Right. So at what point in this protracted process does this now spring to become a metastatic lesion over a controlled proliferative abnormality that's not yet breaking through the basement membrane or doing this, right? So we don't know. Sometimes this can happen very fast. Sometimes

it takes a long period of time because we have these certain cancer cells called cancer of unknown primary. They're highly metastatic. I don't know where the hell they came from, right? We don't know what's, but they're very highly invasive. Then we have other cells that will, well, he had a lesion there a long time for several years. This thing never healed. It was always oozing. It was an eventually explodes into a metastatic lesion. We don't know at what point, it varies from one person to the next. Now, what happens is when the macrophage, we know biology, there are fusogenic cells.

There's massive amounts of biology to show that macrophages are very fusogenic cells. They can fuse with themselves or with other fibroblasts. They can fuse with a variety of different cells. Usually that's part of the wound healing process to facilitate wound healing. But if you fuse with a stem cell that has already defective respiratory systems, you would then dilute the cytoplasm of the cell that you fused it with. And it fuses again and again.

It's a process that takes place. You eventually dilute the normal mitochondria in the macrophage and you replace it with the abnormal mitochondria from the cells that you're fusing with, then leading to a cell with dysregulated growth properties. How many mutations would it take to do that? We don't know because there are some metastatic cells that don't have any mutations, if you can believe it. Deep sequencing, they haven't found any mutations in some of these cells. But they're fermenting and they're spreading. They're growth dysregulated. But wait, how are they growth dysregulated without a mutation? You have cells that are carcinogenic, that are tumorigenic, that have no mutations.

Baker pointed this out. It's like people can't believe this. On the other hand, we have skin cells loaded with so-called driver mutations that never form a tumor. So this linkage between the number of mutations and the type of cancer is just, there's so many flaws in this. So there are cancer cells that have been looked at that have highly invasive metastatic, and they can't find the mutations in there. That's not common, but it happens. So it's a violation to the whole concept. In glioblastoma, there are some tumors that have been found that have none of the driver mutations, none of the abnormalities that you would have expected that are found in others.

So there's a break linkage between mutations. You don't need new mutations to cause a metastatic lesion. That doesn't mean that a metastatic lesion has no mutations. But maybe I'm asking a different question. Okay, so two women have breast cancer. And for all intents and purposes, they have very similar patterns of mutations in their breast cancer. And for all intents and purposes, they have very similar patterns of mutations in their breast cancer. And let's just say, make it easy and say that they're hormonally similar. They're ER, PR positive, HER2 new negative breast cancers. Both women present as stage T2N1, right? So they've got whatever, a five centimeter tumor, if that's still a T2,

I don't even remember. And they've got two lymph nodes or one lymph node. They both have a resection. 10 years later, one of them is still disease free. The other one has died from brain metastases, which were presumably seeded before the primary tumor was resected 10 years earlier. It's not a sloppy surgery where they didn't get part of the cancer. What I'm hearing you say is, yeah, one of them could undergo metastases while the other one did not, even though their primary tumors looked very similar. Is that a correct inference? Yeah, I think that's correct. And what we find now with a number of papers is the needle biopsies that are used to diagnose

the tumors can create a wounded, even a more aggressive wounded situation in the micro environment of the tumor, leading to the phenomenon of inflammatory oncotaxis, which facilitates the fusion. And in other words, by looking at the tumor with a needle biopsy to make the diagnosis, you put that patient potentially at risk for causing a metastatic lesion. And then when you look at the profile, you say, well, this doesn't look too bad. No, not here. But wait, let's say we do that. We're going to immediately resect that tumor anyway. So how quickly does this process take place? Because the wound is between the outside world and the tumor, not between the tumor and the inside world

necessarily, especially if that tumor is going to come out within a few weeks, right? Yeah. We know from a number of studies that needle biopsies can facilitate in some patients the invasion of cells into the local and spread. All right. We know this. This has been reported in the literature for breast, for colon, for liver, for brain. The very act of stabbing this growth can. So then you can get the cells out. Yeah, but I think what's known is that you can seed tumors along the tract of where you do that. Yes, that I understand. But maybe I misunderstood. You're saying that a woman who has a needle biopsy of her breast, who then goes on to get a lumpectomy, has that increased her risk of brain metastases? Well, it wouldn't be brain metastases right away.

It would have to, that brain metastasis, the secondary metastatic behavior, has taken a while. It's not just the brain. But how does the needle biopsy increase the risk of that? The needle biopsy creates a more inflamed condition. That's not just the brain. How does a needle biopsy increase the risk of that? Needle biopsy creates a more inflamed condition. That's why you call it an inflammatory oncotaxis. And this was one of the reasons why they get rid of the morcellation procedure, because this is what was happening. So these women were dying from metastatic cancer, from morcellation. It's kind of a machine that used to be made by Johnson & Johnson for removing uterine polyps. Well, you're taking a polyp and you're grinding it up and creating inflammatory oncotaxis.

Now, there might have been one polyp out of 1,000 that would have this. Right, but that's very different from the – I'm asking a very specific question because here's my fear. What I don't want is anybody listening to this who's got a breast lesion who thinks now they can't have it biopsied? I think that's a very different case than the example of— Well, the evidence is clear in some cases, not all cases. Not everybody who goes under a needle biopsy is going to have metastatic cancer. No, but that's not the question. I mean, what I'm asking is, is a woman, if you take a thousand women, you take—it's a thought experiment.

a thousand women, you take, it's a thought experiment. You take a million women with an identical breast cancer and you take half a million of them and you just do the resection and the other half a million, you do a needle biopsy to confirm the diagnosis. Then you do a resection. Are you saying in the half a million women that had a resection following a biopsy, their probability of metastatic cancer later on is greater? I think so, but I can't be sure because that experiment hasn't been done. I'm basing it on what has already been known about needle biopsies facilitating the spread of the tumor. But again, I'm just being critical of this because I feel very strongly about not causing panic in people, but I think those data are about needle track seeding. For example, like as you said, you have a liver biopsy,

you can get cancerous cells through the tract even after, but that's very different from saying, because that can be dealt with, but this is a very different- Yeah, well, I think this is from what I'm looking at. Now, I look at the brain predominantly, right? You know how many we have what we call secondary glioblastoma. And that is very... It's not uncommon that when you go in and remove a low-grade tumor, that within a shorter period of time, it turns into a glioblastoma. This is the same phenomenon. You're just doing it on a little bit larger scale rather than just through a needle biopsy. So you go in and you take out a low-grade tumor, and all of a sudden within a year or something, you've got glioblastoma, sometimes even less. And you're saying, what the hell happened here? So this

is just a larger- But what's the control for that observation? Well, there- Meaning like another explanation would be the person who has the stage one astrocytoma is more at risk for the stage two, three, or four astrocytoma is more at risk for the stage two, three, or four astrocytoma. From the operation itself, from the provocation of the microenvironment. But without it, we'd have to have a group of those patients who don't undergo surgery. That's right. And you would have to, but who's doing it? Nobody's doing these experiments, but we, but here, here's the situation. What our philosophy is that is if we shrink the tumor,

whether it's a breast tumor, colon tumor, or whatever, if we take away the fermentable fuels and shrink that tumor down, then it becomes a candidate for complete debulking, not diagnosing. Okay. When you take a needle biopsy of a breast and you look at, what are they, why are they doing that? They're doing it for basically two reasons, to try to diagnose what level of cancer you have, and then to give you a gene readout. Like these genes are going to play some role in whether or not you're going to get a treatment, right?

Well, yeah. So those are two. For example, in the case of doing a biopsy before a breast resection, there's value in knowing if a woman might benefit from neoadjuvant therapy, for example, based on their receptor profile. Yeah, but- In other words, it might not just be the gene, right? Right. Like knowing that she's ER- That's true.

Knowing that she's triple positive versus triple negative might change what you do. Yeah, I guess it could. But the bottom line is that why don't you assume that you have a problem? Why don't you just put that patient on metabolic therapy and shrink that tumor down and then do a non-invasive check. Did the borders change at all from the metabolic? And then just debulk it completely. The probability of cure is going to be better in my mind than if you do a needle biopsy without doing the debulking. And just to say, let's look at this. How long after the needle biopsy do you

put that patient at risk for possibly seeding a cell that gets into a lymph node that then can spread out and later that you get brain metastasis, liver metastasis, or whatever else can happen from these cancers? So the question is, why put anybody at risk? If we know we have evidence from the literature to say that is a possibility, why would we want to put anyone at risk for that? Unless the information you get from the needle biopsy is going to be a curative procedure. And a lot of times it's not. It's just for diagnosis procedures. And now today we're using all these gene screens, $7,200 to tell somebody what kind of gene profile. And that

may no longer be relevant after you've taken a needle biopsy from the very tissue that you're doing. Yeah, no, I think that makes sense. I guess I'm a bit confused by the idea. I guess I just don't see- Yeah, these are controversial issues. And I'm looking at it from the point of the biological processes that are taking place from these procedures. And knowing that I've seen literature on lung, I've seen on liver cancer, certainly for brain. I mean, but here's, so, I mean, there are so many potential arguments, right? So you look at one of the most metastatic cancers of all time is pancreatic cancer, right? It's almost uniformly fatal. And yet up until recently, very infrequently biopsied. It's

a very difficult biopsy. You have to do it with an ERCP. No, that's true. So yet, in other words, you can still have incredibly aggressive metabolic cancers, which are not biopsied often. And then conversely, you look at a GBM, you look at the cancer we're sitting here talking about, a very aggressive, one that John McCain just passed away from. Well, that's, I mean, that's only locally metastatic. It never leaves the CNS, does it? Oh, yeah, it does. Where does it go?

It goes to bone. It goes to liver. It goes to, nobody looks at the- What percentage of patients die from, or- Not many, but when they look, they find. This was one of the big things. This is how we discovered the macrophage origin of the cancer. We started looking and say, how many people do autopsies of organs on people who've died

from glioblastoma? And what did you find? There's 100 articles in the literature with metastatic GBM to various organs for people dying. People say, well, it doesn't happen that often. You know why they die the GBM? Before they start recognizing they have metastatic liver cancer. But when you look at livers and kidneys and these other organs from patients who have died from GBM, those studies that have looked have found cancer. So clearly, these cells are coming out of the brain, and

they're getting into the other organs. The problem is the patients aren't living long enough to have a problem. Well, who's worrying about the guy's liver when his brain is starting to swell up from all the treatments they're giving him? I mean, 12 months, most people are dead. But there's over 100 articles in the scientific literature showing outside, I call it extracranial metastasis of glioblastoma. So it's not that it's – and people ignore it. It's like knowing that the mitochondria damaged in, in cancer cells, people ignore it. Well, I guess that would be, I'd be, that'd be a more forgivable thing to ignore because I'm not convinced it necessarily changes

the story. The mitochondrial one is a much more interesting question, right? If, I mean, that to me, of all the things we've talked about today, Tom, that's the one that kind of has me scratching my head the most and wondering in 2018, how are we even having that? This is this this should be something that's not debated. This should be sort of like this would be like debating whether DNA is necessary to make RNA like that. That discussion was settled in the 50s. And anyone who disputes that now is sort of, you know, disputing the shape of the earth. and anyone who disputes that now is sort of disputing the shape of the earth. So I guess to me, given the stakes here, I would love to figure out why people aren't answering this question. Well, let's look at the situation from even a greater distance. In the United States, we have over 1,600 people a day dying from cancer. I mean, this is horrific, right?

There's over a half a million people a year, 1,600 people a day dying from cancer. Obviously, there's something seriously wrong. There's something massively wrong with what we're doing with this disease. You know, we talk about needle biopsies, we're talking about this, we're talking about that. The issue is we had 1,600 people a day dying. Why are all these people dying from cancer? So it's either we have a fundamental misunderstanding of what the nature of the disease is, we're mistreating it, we're treating it as something that other than what it actually is. So the debate that you mentioned now is that the results of the dead people are the consequences of the fundamental misunderstanding of the process of the biology of the disease. What I'm arguing is that now understanding the biology of the disease,

we have the potential to drop the death rate by more than 50% in 10 years. There's no question about it. If you stop doing half of the stuff that we're doing to these cancer patients, looking at the biology and the nature of the disease, how to best go about this strategically, I think we can drop the death rate by 50%. We're doing stupid things, right? Needle biopsy tumor cells for genetic profiling that has no relevance to the nature of the disease. That's just one. But just to go back to that, because I'm sorry, I really want to make sure people aren't going to stop refusing their biopsies. But have we seen an increase in the rate of metastases in the era of needle biopsying for genetic sequencing? I mean, we could go back and look at the death rate from cancer 50 years ago before anybody was doing this and it was the same.

Yeah. Well, I think that we've probably, I don't want to say, I just want to say that every year we have more and more dead people. This is, and the increase is faster than the general population. Okay. So we had 3.8% increase in death. Is that actually true? Is the age adjusted population adjusted mortality of cancer today higher than it was 50 years ago? I think it's about three or 4% lower. Well, I just did the last five years. Okay. From 2013 to 2017.

But to test this hypothesis, we'd want to take an even longer time period and go more extreme as far as like, well, you know, I mean, I mean, every year, there's no year that we have fewer. They're always coming. The dead people are piling up. So when I look at the numbers and I say, okay, what was the percent of population increase in the United States over the last five years? And according to the demographics, it's 2.9%. Okay.

Over the same period, how many cancer deaths? Right. But again, I don't know my epidemiology well enough to make this case, but I'm going to try anyway. Isn't the growth in population more a function of the input of people, meaning birth rate, rather than the people who are getting cancer, which are the older folks? Well, we have younger people too, right? Right.

But the majority of cancers are older folks. Yeah, majority of cancers are older folks, for sure. So I'm not sure that that population argument would answer that question, right? Well, maybe. There's always a guy you can find. I think all you have to look at is the numbers of people that are dying from the disease. I mean, that's a fact. No, it's a fact and it's a tragic fact. I guess a 50% reduction in the mortality of this disease in 10 years is a very bold statement given that we've seen about a 3% reduction in cancer mortality in 50 years. Yeah. Which I think you're arguing is unacceptable and understandable. Well, you know, yeah, I'm looking at it from the tragedy. In

China, it's 8,100 people a day dying from cancer. I mean, that's the number over there. Maybe I've the bigger population. But the problem, it's now surpassed heart disease in their country. Clearly, it's not whatever we're doing. And yes, 50%, if you did what we think you need to do and to manage this disease, looking at it from the biology of the disease, you will, I think, I would not be shocked if we had a 50% reduction in 10 years. So normally I ask people what their dream experiment would be, but I want to ask you two. I want to ask you this question twice. The first one, the first time I'll ask you this question will be the easier one because it'll be the clinical trial. So what would be the dream clinical trial to test the hypothesis that says we can reduce the mortality of cancer by 50%?

What would you want to put head to head to definitively ask that question? So what we do right now is if we do metabolic therapy at all, okay, we do it at all, it's either standard of care versus standard of care plus metabolic therapy. We're missing the critical control group. Metabolic therapy without standard of care. What are we doing to these people? So tell me what the experiment would be. Let's use breast cancer as an example. Okay, breast cancer. So you have your standard whatever you're doing today. You got a lot of people dying of breast cancer, met Okay, breast cancer. So you have your standard whatever you're doing today. You've got a lot of people dying of breast cancer, metastatic breast cancer. So we're going to now take metabolic therapy, and we're going to combine it with standard of care, which is what the group in Turkey.

And how would you integrate that? Let's talk about how you would do it, not necessarily how it's being done. How would you, for the purpose of the experiment, integrate standard of care and metabolic therapy? Okay, so we would use the chemo and we would have people on metabolic therapy, which would be lower. And you would do those in parallel? You would have some patients that would be treated only with the standard of care, which would be our control. And then we would have people treated with the standard of care plus reducing blood sugar, elevating ketones, and targeting the energy metabolism, which we can do. And would that include things like metformin or DCA or other things like that? It could include that.

Hyperbaric oxygen? Yes. Yes. And that's what we're doing in Turkey. So it's basically standard. However, in Turkey, we're doing the lowest dose of chemo that we can use to still be in compliance with the law. And if you get rid of... Now,

the control... And now your metabolic therapy alone group... Metabolic therapy alone group. What would that group be? That group would be the press pulse concept. So we down-regulate the glucose first, shrink the tumor up, make the microenvironment less inflamed, less angry. Then we... Specifically tell me what would be in that. So you would... These patients would be on ketogenic diets? First, we would lower their blood sugar gradually, depending on the status of the individual. So you'd go into lowering their blood sugar, elevating their – putting them to therapeutic ketosis, essentially. So a lot of these people also have a multiple other series of metabolic abnormalities. They have type 2 diabetes.

They've got triglyceridemia. They have all kinds of other things besides having cancer. So basically, by bringing them into a state of therapeutic ketosis, you are- And how do you define that? Is that defined by the amount of glucose and ketones? It's by the glucose-ketone index that we published. We published the paper on this. And what's the ratio that-

It's a ratio of about close to 1.0 or below, if we can get it. This is where the millimolar of ketone and the millimolar of glucose are about the same. And that people hit that somewhere between three and four, I'm guessing. Days after? No, three to four millimolars tends to be the place where they're about the same. It could be. It could be. It depends on the individual because some people have higher glucose, higher ketones, and yet they still have the same ratio. So some people have very low glucose and not that high of a ketone, but it gives them the same ratio. So some people have very low glucose and not that high of a ketone, but it gives them the same ratio.

So the issue is get your ratio. The only time I've been able to be at one-to-one is when I'm not eating anything. Yeah, well, it's variable from one person to the next. And then the other thing too, we have to be very careful about is a lot of cancer patients, very hard to get into one. You're a young, healthy guy.

Guys that are young and healthy can get well below one. Women are better than men. We've done some studies. So basically, but cancer patients are freaked out because they have anxiety, and anxiety elevates corticosteroids, and you have a tougher time bringing your... So we also institute with the press, besides ketone supplementation, as Dom D'Augustino has been telling, and the ketogenic diet. And then we have stress management, which includes music therapy, yoga therapy. There's a variety of ways to reduce emotional stress. And that's a very important part of the management. You have to let the patient know that their disease is not terminal, that their lowering of the stress is going to make the medicine work. So once we get the patient into metabolic ketosis,

now we have options. Now we can start using insulin therapy to bring the blood sugars down lower. We can put them into hyperbaric oxygen, which creates oxidative stress predominantly in the tumor cell and not in the normal cells. The normal cells are burning ketones. That reduces oxidative stress. When you say insulin therapies, do you mean actual insulin? Yeah. We're testing that now. The Germans used to do that years ago, but we don't think we have to put people into metabolic comas to do this. We think we can do it without it. We're testing it now. So I'm working on it now. As we speak, we have these experiments going next door. So the question is, you don't want to use insulin therapy unless you're in therapeutic ketosis. You

don't want to go into a hyperbaric chamber unless you're in therapeutic ketosis. You don't want to go into a hyperbaric chamber unless you're in therapeutic ketosis. And then we would pulse with drugs that target glutamine. And together, you're removing the antioxidant capacity of the tumor, making it vulnerable to hyperbaric oxygen. How much can these drugs lower local levels of glutamine? Enough to slaughter the tumor cells. But I don't know enough about this. Is that a 50% reduction that's necessary to do that?

Because you're getting about a 50% reduction in glucose based on the therapy you've described. We want to lower the glucose even further because you can do that. And with ketones, correction, with targeting glutamine, it's got to be pulsed because you can't chronically reduce glutamine to the availability to the physiologist. But acutely, how much do you lower it? We can lower it quite effectively. We can shut it. Well, don't forget, the cancer cell is absolutely dependent on this fuel. The normal cells, they can burn the ketones also.

So they're not going to be energy deprived completely. Whereas the tumor cell will be deprived energy completely. Are there some cancer cells that preferentially utilize ketones? No cancer cell can use ketones. You have to have a good mitochondria. And a cancer cell that would have some oxidative capacity, a small amount of oxidative capacity, could burn some ketones. But most of the most aggressive cancer cells can't burn ketones because they're mitochondria defective, that you need a good mitochondria. That's why it's a selective. It selects for

enhancing the vitality of the normal cell while putting the cancer cell at a competitive disadvantage. So the ketones are not to kill cancer cells. They're to of the normal cell while putting the cancer cell at a competitive disadvantage. So the ketones are not to kill cancer cells. They're to provide the normal cells with a fuel as an alternative to glucose, that the tumor cells can't use the ketones. And I've done many experiments like this. If you take cancer cells and grow them in a dish without glucose and glutamine, just ketones, they die. But normal cells don't.

The normal cells can survive on the ketones without the glucose and glutamine. So it's very clear that the tumor cells can't use it. And as I said, you have to have a good mitochondria to do this. So we're selectively marginalizing these tumor cells because of their metabolic incapabilities. But it has to be done strategically over time. And where does the hyperbaric oxygen fit in? Is that part of the pulse, obviously?

Yeah, that's a pulse therapy. And how much hyperbaric oxygen fit in? Is that part of the pulse, obviously? Yeah, that's a pulse therapy. And how much hyperbaric? We want to try to replace radiation therapy with hyperbaric oxygen, because the mechanisms of cell death will be very similar. So how many atmospheres? We do it at two and a half atmospheres. For how long? Well, we were doing it for 90 minutes every day, something like this. So it's designed

to put oxidative stress, killing the tumor cells by oxidative stress, the same way a radiation therapy would work. Radiation a lot of times doesn't work because the cells are in a hypoxic environment. So why are they in such a hypoxic environment? Because they're fermenting. They're blowing out all this fermentable fuels into the waste products. Got to clean that all up. That microenvironment has to be brought back to a normal state. And therapeutic ketosis, we published several papers showing that it's a powerful anti-inflammatory

therapy. It makes the microenvironment less inflamed. It's pro-apoptotic. It's anti-angiogenic. So you're killing all these bad blood vessels and replacing them with normal blood vessels that the normal cells will be able to use. So it's reconfiguring the microenvironment while putting stress and killing tumor cells. Now the tumor becomes more and more vulnerable.

And now it becomes more and more damaged by drugs that are going to chip away at the surviving cells. It's not something we're going to go in like a bull in a china shop. It's going to be a gradual degrading of the tumor. And where does the surgery take place here? Is the surgery taking place before all of this happens? No, the surgery would take place at some midpoint. The midpoint would be where the surgeon now looks at the tumor and says, I can take care of this. It's not going to be a diffuse mass.

It's not going to be an angry inflamed thing where you have to cut out half the guy's colon in order to get what you think is the part of the cancer that's it. No, this thing will be now much more shriveled. We've seen it. It's much less angry. It's more demarcated. You can see it in the histological slides. You can see what the hell happened to this tumor. How come it's smaller? How come the margins are more sharply defined? Because you took away the inflammation that was being driven by the fermentation fuels. So you're shrinking this tumor down. Now the surgeon comes in and can potentially cure these people that would be maybe not curable in the past. So this is why I'm saying we can reduce the death rate by 50% if you view the tumor as a metabolic problem rather than a genetic problem.

The gene mutations are all downstream epiphenomenon. They're red herrings. Even Vogelstein, who still claims that this is a bird, Vogelstein from China, he still claims it's a genetic disease, but we're never going to cure the disease by targeting the genes. There's too many mutations. It's all this kind of stuff. But we can do that with metabolic therapy.

We can actually eliminate the cancer based on metabolic therapy. It's a process. Who's trained to do this? No one. I mean, we need physicians to be trained to do this. They've been used to train to give high doses of radiation without killing the patient or poisoning these poor people with drugs that are very toxic and keeping them alive so you don't die from the treatments. This is absurd. Why are you using radiation and chemo in the first place? Well, we have to stop proliferation. Okay, well, if they can't generate energy, they're going to stop proliferating. They're going to die. What is the experiment, the clinical trial that you're involved in in Turkey that you've alluded to? Yeah. So what we do, my colleagues in Turkey do,

is they use chemo, but they use the lowest possible dose. Is it for breast cancer? All cancers. In fact, the results are the same. All cancers are the same disease. They're all fermenters. So once you knew that they're all dependent on these two fuels, then all you have to do is target the two fuels to put them at risk for elimination. The question is how can you target the fuels without harming the rest of the body, and that's the press pulse concept.

fuels without harming the rest of the body, and that's the press pulse concept. So we know we can press things constantly without harming the body, but we have to pulse the glutamine issue because we don't want to deprive our normal immune system and gut systems of the very fuel needed to provide normal physiology in those tissues. So this is why we have to pulse the glutamine issue. How many glutamine drugs are there? Well, there's some coming all the time, but the one that works the best for us is Don. Are there any that are in clinical trials in the United States? Yeah. There's a couple. There's a name. There's a few names of them. They target various aspects of the glutaminolysis pathway. The problem is we have a drug that's called, it's a dirty drug. It hits multiple pathways of glutamine metabolism, and it seems to work better than all the other

drugs, at least from our perspective so far. Which drug is that? This is Don, the 6-norleucine. It was used in clinical trials years ago, but it was partially effective. But they weren't targeting. They weren't doing the full metabolic approach. If you don't do all the parts of the problem, the horse is going to get out. It's still not going to be effective. And today, no one anywhere on the planet is doing the kind of a therapy that we think need to do to make this all work. Now, there's bits and pieces of it. And then what are the drugs that are in current clinical trials that are targeting glutamine? Well, there's a BEPTS, I believe, an acronym for another very complicated structure.

And then they're making DON analogs that are supposedly less toxic. What we find is with the ketogenic diet, Don becomes far less toxic. So you can actually use far lower doses. So I was talking to somebody the other day, is it better to wait for a pharmaceutical company to build a new drug to target cancer, or is it better to develop a way in which a previously very effective drug could be less toxic? And both of them, the end result is the same. You're going to get something that's going to work far better than what was previously available. So how many clinics in the country, in the world, are treating cancer as a metabolic disease

using a strategy that will take away the two prime fermentable fuels for the disorder? And the answer is no one. No one's doing this. But this trial in Turkey is doing this? Well, they're not targeting the glutamine. So they're doing these other processes. So it's the glucose, the ketones, the hyperbaric oxygen, but not pulsing with glutamine, not the anti-glutamine. Not doing the glutamine. Nobody's doing the glutamine. We tried doing that in our Egyptian patient that we published recently. We used chloroquine and we used EGCG, which is a green tea extract. But they're not as powerful in the clinic. Now, that poor guy, he just passed away.

We were devastated by this. We published the paper. He lived 30 months, which is far longer than most people with a glioblastoma. He was doing really well on metabolic therapy. We pushed off the standard of care for three months. So we did surgery after three weeks of therapeutic ketosis, debulked the tumor, most of it, because you never get all GBM. And then we were forced into the radiation therapy after three months, even though the guy was doing remarkably well. So we said, why are we irradiating? We have to, because it's part of the standard. This was in Alexandria, Egypt. And then a year later, he starts developing, or it was six or eight months later, he starts developing a headache. His head starts to swell. And they did the compression, the bulking, and

they found, looked at the tissue. There weren't any tumor cells. He was dying from radiation necrosis that he took from the radiation. So this is why I'm very much against it. I think we're not going to make any major advance in brain cancer until we stop irradiating people with the brain because you're creating a bigger problem. And this is leading to the demise of all these poor patients. The survival after radiation is almost zero. And in my mind, it's doing in part to the radiation

that we're giving to these people. So whether they're dying from the tumor or radiation necrosis, they're going to be dying. They shouldn't be doing that in the first place. So the standards of care have to be dramatically changed in order to improve overall survival. So when I say we can drop death rates by 50% in 10 years, we're not only dropping death rates, we're massively increasing overall survival and quality of life at the same time. death rates were massively increasing overall survival and quality of life at the same time. So I have a lot of anecdotal information with people who have been treated with metabolic therapy, part of it.

They're living far longer. Their quality of life is much better. And when they die, they die in a very peaceful way. And some of my clinician friends have been telling me this, these guys that are in these metabolic therapies. Their quality of life is really good up until about two weeks before they die. Whereas the people doing standard of care never live as long and their quality of life is horrific. They're living there, they're incapacitated. So do you think that metabolic therapies are, offer the potential for cure or

just another therapeutic option? Because if you want to reduce the death rate by 50%, there's no lead time bias slash therapeutic extension that's going to do that. That is a paradigm shift in cure, not treatment. I think it's both. I think you're going to be able to extend dramatically overall survival. You're going to improve dramatically quality of life. And how do we know if we're cured? The issue is that if you die from a heart disease at 85 and you had cancer when you were 50, so-called a terminal disease. No, I mean, I think we could pick something simpler than that, right? If you are 10 years disease-free, to a first-order approximation, you're cancer-free, right? If you had colon

cancer 10 years ago and 10 years later you die of a heart attack i think it's safe to say you died of heart disease even if on a autopsy they find dormant cancer cells well you know here's a situation if you take standard of care and you live 10 years and or like you said and you drop dead of a heart attack so is that heart attack was that heart attack the result of the cancer or the treatment? You also have to put into perspective what effect does the treatments have on your overall long-term survival as well. So Dana-Farber down here just opened up a branch of medicine called cancer survivor medicine. It appears that many people treated with standards of care are suffering horrifically from all these other kinds of diseases they never had but for the fact that they were treated with all this toxic stuff. So we would eliminate that. Why would you, if you're in therapeutic ketosis and you're, it's unlikely.

But I'm still like, what's the proof of concept that the metabolic therapy can lead to a cure? So is your hypothesis that this gentleman in Alexandria, if he hadn't been, if he hadn't undergone radiation for the GBM, your belief is he could have actually had a cure? I don't know because we can't know. Like you said, we'd have to wait 10 years to know that. So if we were to institute an aggressive metabolic program for managing cancer. But it seems GBM would be the place to do it, right?

Because it's, you know, it unfortunately is such a uniformly fatal cancer. And it's fatal because of the treatment that they're giving these, this combination of what they're doing to the patient as well as the tumor. The problem clinically, right, is that the mass effect doesn't give you a lot of flexibility to delay surgery. So between corticosteroids and radiation, when a patient, some of most patients present with GBM, not as incidental findings, they have symptoms from the mass effect. So we have to be sympathetic to the clinicians in the conventional pathway who are saying, look, I got Bob here. He's

complaining, he's got, you know, hemiparalysis and he's got a GBM. The idea that we're going to wait a month to put him on a ketogenic diet when I need to either cut that thing out now or radiate him or put him on corticosteroids. So in other words, this is going to be a very difficult thing to study. Well, it's a judgment call on the part of the neurosurgeon, okay? So he looks at the data. Do we have a watchful waiting period?

This is, I've spoken to many neurosurgeons, a lot of my friends. I said, what's the stat? What do we do here? He said, occasionally, if you have brain herniation possibility, the patient can be dead in a week if we don't do debulking. That patient has to be debulked.

All right, but you don't have to give them steroids. You can just do debulking. Steroids will shrink the edema. Of the three, what would be the most evil in your mind? Meaning metabolically evil, the radiation, the corticosteroid, or the surgery? Oh, clearly the steroids and the radiation. So then it would seem to me that every GBM patient should go and have the resection and then undergo metabolic therapy, even though they're not technically going to be free of

disease. I think this is the strategy. How long the watchful waiting period is will give the neurosurgeon an opportunity to do a greater debulking. And there's 100 articles in the literature showing that the longer you live longer on debulking, the more you can debulk the tumor. So if we can shrink the tumor down like we did on our Egyptian patient, we waited three weeks. We put him under incredible therapeutic fasting, water only, 900 ketogenic diet. They did a very awake, good- 900.

900 calories, kilocalories. Yeah, but not water only, you said. Water for the first three days, water only. I see. And then we transitioned him. He did an awake cradionomy. It was done very well. Then we pushed off the radiation therapy for three months.

And we didn't want to do that because the tumor was looking really good. He had a correction of the midline shift. He was in good shape. So I think he suffered from the radiation. I think he didn't survive because of the radiation treatment. Do you think that GBM would be the best histology to study this in? Oh, yeah. Because as you said, the survival is- You're going to see a signal if one's there. Yeah, because it's, as you said, the survival is- You're going to see a signal if one's there. Yeah.

And then I've spoken to a lot of my friends who think that, okay, we have to debulk immediately, then we're going to go to metabolic therapy. We can push it off for two weeks and then do metabolic therapy. The thing we have to do is we have to eliminate radiation. I think radiation is part of the biggest part of the problem. I think if you're doing metabolic therapy, you should eliminate radiation right away. I have no doubt about this. This is absolutely, in my mind, a problem.

And this is one of the reasons why there's so few people surviving. It's because you are radiating this. If you didn't irradiate, you could survive a lot longer. I think with metabolic therapy, you can double, triple the amount of survival. How do we know this? Because those patients that I know

who rejected radiation and chemo, took surgery after two years or a year, are doing well. They're out four years. So clearly – With which histologies? GBM. There are GBM patients alive at four years? Yes. Pablo Kelly.

In fact, I'm going to be there next week. He's going to be sitting in the audience. Is this published? No, it's not published. But the guy has all the documentation. It's just that it's not yet published. Why? Because I haven't sat down and wrote it up yet. What would be more important than writing that up? Writing another paper up that I thought the guy was going to live just as long, but he was already- No, no, no, no, no. Look, that guy was one guy alive three years. If you have a cohort of patients

that have been alive for four years with GBM, I don't know what would be more important than writing that out. Do I? I don't know of anything more important either. But you don't forget. We should stop this podcast now so you can start writing that out. Well, I'll talk to him. In fact, he's going to be giving a lecture after my lecture. Because that's, I mean, that's really where you want to be able to generate interest on a clinical trial.

Okay. So how many people, he's a young guy, 25 years old. He says, I don't want radiation. I don't want chemo. I don't want old. He says, I don't want radiation. I don't want chemo. I don't want any of that stuff. I don't want surgery, he says. Oh, you're going to be dead in three to six months. That's what they told him.

It's all in the news. It was in the newspapers. I gave him the stuff on the metabolic therapy. I didn't know he was going to live that long. I thought he was just going to live a few extra months. He comes back and he says, I'm still alive. And there's a big newspaper article in the British newspapers about this guy who rejects all. So after two years, he decides, he had an alive. And there's a big newspaper article in the British newspapers about this guy who rejects all.

So after two years, he decides, let me, that he had an inoperable glioblastoma that now became operable after metabolic therapy. So they debulked it. And now, after another year, he doesn't have any tumor left. And he never had radiation. He never had chemo. He had surgery, very delayed. And they did a histological analysis after the debulking and said, yes, you did have a GBM. Because what a lot of people say, if you've lived that long, you never had a GBM. That's bullshit.

The problem is just that, I mean, you're creating a situation that leads to the demise of those very people that you are trying to help. And when you irradiate the brain, you free up massive amounts of glutamine by breaking the glutamine-glutamate cycle. So those tumor cells are sucking down massive amounts of glutamine. And then you give the steroids to reduce the edema, which then elevates the blood sugar.

So I was going to give you two experiments, two dream experiments. So the second one would be going back to sort of the more fundamental premise of this, which is what if resources were, you know, no constraint, how could one unambiguously make the case slash test the hypothesis that despite structural abnormalities in the mitochondria, the production of lactate and the fermentation is not purely for respiratory compensation. In other words, we talked about this idea that says you can have a structural deficit but still be functionally good enough. How can that hypothesis be tested? Because that seems to be one of the central arguments here. Well, I mean, there's several ways we look at this. If a cell

can live with ketones without glucose and glutamine, you'd obviously have some mitochondrial function that would keep them alive because they wouldn't be able to ferment. But let's like, we're in a resource unconstrained world. So what are the dream experiments that would test that in humans? I mean, in vivo, because a lot of these mechanisms would be tested in vitro, because you can't do those kinds of experiments. But the metabolic therapy that we have designed, Dom D'Agostino, myself, Joe Maroon, who's the team surgeon for the Pittsburgh Steelers, neurosurgeon, George Yu, who is a prostate oncologist, prostate cancer oncologist. We all sat down and we built this press pulse therapy. Okay. So if you deprive the tumor cells of their fermentable fuels and you kill, and you essentially eliminate, I can't detect any more cancer in your body.

That's based on the biology of what the problem is. All right. So the dream experiments are to ferret that out mechanistically in vitro. So to prove that this is the case, and we're doing that right now. When we target these things, these cells die. So, you can put them in where normal cells wouldn't die. So, clearly, what's going on here? I mean, it was shown in many papers. In fact, back in the 30s and 40s, beautiful papers showing that the respiratory system of tumor cells is massively compromised.

Okay, if that's the case, then they're surviving on fermentation. There's no other known biological system in the world that can provide alternative ATP. But yet most people don't agree with that statement. So that's what I'm asking is what experiment could take the debate out of that very important question? Okay, so they don't believe it. If I look at the data and you look at the data and we both come to the same conclusion and this other guy looks at the same data and he says, I don't believe it. Then it tells me the data are not convincing enough

if everybody's acting in good faith. Well, then do you have to ask about what's good faith? Or what's better data? Okay. Okay. Look, here's the way I look at it. If science is a human activity, okay, there are people who say things that are not true and everybody believes it. Right? Right? All right. So I look at something. I'll refrain from making all political jokes right now. Right.

I understand. But I understand completely. But the issue here, of course, is that you have, it's one thing to say, okay, we had a review on a paper that we know there's a massive biology on the role of cardiolipin in controlling the electron transport chain. I mean, there's dozens and dozens of papers on this, and a molecular biologist, I don't believe it. Well, what don't you believe? What part of this massive amount of scientific evidence that you don't believe i'm unfamiliar with cardiolipin therefore it can't be right well

that's not the reason to discount the right right and when you write the paper up why would you not cite pete peterson's massive compendium of evidence saying mitochondria are abnormal and you say mitochondria is normal well how does that how does that jive with the massive amounts of evidence to say that's not? What I try to do in all my writings, I never try to ignore an alternative fact to what I'm saying. I try to say there is a fact that I'm not yet completely clear about, but I'm not going to ignore it. Okay?

You'll find in the scientific literature today, in the top journals, that they're ignoring massive evidence that don't support their position. And that's one of the problems. And like, you know, we were saying that this problem in cancer, all these top journals sell science nature, you know, 50% of them, up to 50% of the article can't be reproduced in other people's labs. This is a crisis in the field. What's going on here? So you're ignoring massive evidence that doesn't fit your particular mindset.

So you will just discount it. I don't think it's any different than the geocentric, heliocentric model of the solar system. The Catholic Church refused to believe that the Earth was not the center of the solar system, despite all the evidence that said it was. They just refused to believe it. We have the exact same thing in the cancer field. You have massive evidence showing that the mitochondria are structurally and functionally dysfunctional. I don't want to believe it. What can you do about that? What can you do about that when you have the evidence to show that and you choose to ignore it?

Is that any different than the heliocentric, geocentric system that we had? The difference today is that we have 1,600 people. Yeah, I mean, it's slightly different, right? But I don't want to get into the details. No, it's a fact. You have fact. Yeah. And don't forget they didn't... Well, but I think the Catholic Church was basically relying

on a religious framework as their counter-argument. Of course. And so their belief system was formed by something different. I think in the scientific... Yeah, but when Galileo said, please look through the telescope to document that Copernicus was right, they didn't want to look in the telescope.

They didn't want to look in the telescope. So because it would disrupt their worldview. If you've just put the list- No, I mean, I think that's a fair statement, I guess. Again, I come back to this through the lens of, I'd love to know what the experiments are that could, because I view it as a stalemate. If you're looking at a body of literature and they're looking at a different body of literature, and every time everybody looks at everybody else's body of literature, they say, and they're looking at a different body of literature, and every time everybody looks at everybody else's body of literature, they say, well, there's an alternative explanation for this,

then we're making no progress. The answer to me is collaborate, generate new experiments. That's why I think knowing the biology of the disease as well as I think I do, and we never can know completely everything because every human being is a different entity. You're dealing with a different entity. If we can increase overall survival and improve quality of life, massively advance to what we're doing today, because we use the strategy based on what we understand to be the biological problem and the results support that, then I think that's the

advance. And glioblastoma would be a wonderful- So speaking of that, realistically, when do you think that case report of these four-year surviving cohorts will be published? I'm going to try to, when I talk to him over there, I'd like to speak to the very physicians that actually took the data from him, from Pablo. How many patients are in that cohort? Just him. Oh, there's just one guy who survived four years. Well, one guy because he rejected- No, I understand. I misunderstood. I thought there were several patients. Well, there's Andrew Scarborough who initiated a first couple of radios and said, no more of this. He took no

radiation, no chemo. He's still going. He had a stage three astrocytoma, which is also quite lethal. Then there's Alison Gannett. She's on the news. She has a website saying that she survived GBM without this. I have other anecdotal reports based on what people have told me. One poor guy, he had no money, no insurance, so they didn't want to rate it because they wouldn't be able to get any revenue from this guy. He just did ketogenic diets way back before even I was talking about it. And he's still alive 16 years. So, so there- But what was the, did they eventually do surgery on him? They did surgery, but they didn't do anything else. But, so what is it?

So again, these are anecdotal, but with Pablo, we have data. We have clear data from him. So it's not, it's not like we don't have data from him. You know, we have a lot of things, a lot of these things people would say, well, you can't do this. You can't, you can't do what I'm asking you to do because it violates the standard of care. The standard of care should never have been written in granite. It should be flexible. If you have something else that comes along that might be better, you'd think there would be an enthusiasm. No, we have not seen

that. We try to get this through the University of Pittsburgh to try to do this. The advisory board, right? The IRB. The IRB refused. Okay. So they would only might consider metabolic therapy after standard of care fail. What standard of care fails all the time? Why don't you try metabolic therapy as an alternative to standard? No, we can't do that. Why? Well, because we can't do that. Why? Because we can't do that. That means there's inflexibility. So we're up against firewalls after firewalls after firewalls to try to change the way we continue. We're doing all the gene screening, mounting to nothing because cancer is not a genetic disease. So we have all these firewalls that are preventing us from moving forward the way I think we need to be moving forward.

For a GBM patient, what do they have to lose? There was a paper that just came out the other day from out of British Columbia, Canada, carefully looking at survival for GBM. They said it's woefully similar to the 1926 Bailey and Cushing paper, for Christ's sake. I mean, what's going on here? You mean in almost 100 years? John McCain's size, 12 months. That's no different than if he had the cancer different than if he had the tumor in 1926. So that tells us we have a serious, serious problem.

And I'm offering an alternative that might be able to change that. What is wrong with that? Why would I be attacked for something like this? So you tell me. I have to know what's going on here. So I go up and I say, you can't irradiate the brain. Oh, you got to do it. Here's my parting shot of advice, Tom, which is it's worth nothing, but your passion is palpable. I lost a friend to GBM. So the very first person in my life that I ever knew that died of cancer died of a GBM. And I was with him almost until the day he died. And it was the saddest thing to

see the last year of his, he lived 18 months and a year of it. He didn't, he couldn't see. So, you know, you talk about what, what is it like to be a 19 year old kid who can't see anything? And I look at, uh, it's actually one of the saddest stories. I don't even want to tell it. It's so upsetting. Anyway. Um, I get it. I think my advice would be the following. Whatever you've been doing. Hey, the phone rings. What the hell? Perfect time.

Whatever you've been doing is not getting through. You got to do something different, right? So there's a quote by someone who's escaping me. It's like the definition of insanity is doing the same thing over and over again, expecting a different outcome. You got to do something different. Well, I don't know what it is. If I had that advice, I'd offer it. But I'm just saying you've got to try a new approach to get that clinical trial done.

Yeah, well, don't forget I'm a professor in an academic non-medical school environment. So we design the preclinical studies that allow the clinicians to then adapt it to their patient population. the clinicians to then adapt it to their patient population. So this is what, there's very, we're the only, one of the only groups in the world that are actually doing bench to bedside real research, because I have, I have tentacles for all these different clinical things. It's, I get it. All I'm saying is the current, you're, you're, you're abutting a resistance and I, you've got to go around it. You've got to, you've got to go around it. You've got to go around it. And it might be that you get enough of these case reports published that it becomes very difficult to ignore. And people would say, look, here's a concession. We're going to do surgery immediately

and then follow with metabolic therapy. Because I think you're going to have a very hard time saying no surgery, no corticosteroid, no radiation. I just don't. I think that's metaphysically not going to work. I didn't say that. No, no, I know. That was a judgment call on the part of the clinician. But I'm saying if you're willing to accept immediate surgery but delaying or postponing radiation and or corticosteroid therapy until they are necessary either due to medical progression and or symptom

control, you have a chance. And so, of course, the question then is you've got to find advocates on the other side of this ledger, but the ledger meaning in terms of the thinking about this disease. Yeah, well, I agree with you. So what would you suggest? What's the roundabout approach? You're in the field. A great discussion over that scotch that you promised me before we started this podcast.

See, see? We're trying to do this, right? Yeah, yeah, yeah. We need guys like yourself and others to get the word out that there are alternatives and that who's going to be the bold one. and others to get the word out that there are alternatives and that who's going to be the bold one. And I know I'm speaking to now people who want to set up these special clinics, special kind of treatment clinics where we can bring everything under the same roof. So you don't have to run over this place in that place. We take the patients. This will happen. It will happen because people want to live. Yeah. Look, I mean, that was going to be my, if, if, if forced to give

one idea now, cause I don't, I don't think I know the answer, but if I were going to give you one suggestion, it would be do this from a position of pull, not push. So right now you are pushing this idea. In the end, the results were so dramatic that the parents of the children, a third of whom now no longer suffer from epilepsy, another third of whom have at least a 50% reduction in epilepsy, they basically become the voice of reason. And I think that's a part of the reason today, not the only reason. a part of the reason why today the only place in sort of the traditional medical view where a ketogenic diet is viewed as a legitimate first-line therapy for recalcitrant disease is in epilepsy. Now, I think there will be a day when that expands. So what I would hope is that there's a network of people, family members probably, who have lost people to GBM who would become the ones that would be your mouthpiece, right? Would become the ones that would say, you know what? I'm tired of the fact that my loved one died in nine months seemingly in vain.

And there's this body of evidence which, look, admittedly at this point is small and is uncertain. But nothing in science is certain, but they're offering an alternative. I want to know that that could be tested. Yeah. And the thing that kills me on these private foundations and things, their advisory boards are made up of physicians that subscribe to the gene theory of cancer. So when the patients and their advocates hear about this- So here's my second piece of advice. I know I said I wasn't going to give you any advice. My second piece of advice is you're fighting an uphill battle. You don't need to. It could be a genetic disease and a metabolic disease simultaneously. I would argue that cancer is when you think about the three diseases, the three disease processes that are going to kill all of us sitting here right now in this room, it's going to be atherosclerotic disease, neurodegenerative disease or cancer. Statistically speaking, that's how we're

going to die. Of those three, I don't think there's any that are more evolved and complicated than cancer. I think cancer is by far the hardest of those. And therefore- Well, now there's where I would disagree strongly. Well, but that's too long a discussion. The point is, whether you agree with me or not, let's argue the following, or let me state the following and or posit the following. It's a very evolved condition, and therefore you could have genetic pressures, metabolic pressures, immune pressures that all predispose to it. So I don't think it has to be an either or.

I think metabolic therapies could be valuable whether or not the genetic ideas of cancer are right or wrong. So to me, it strikes me as an unnecessary fight, right? Instead, the answer should be, look, we should have medical oncologists, radiation oncologists, surgical oncologists, immuno-oncologists, and metabolic oncologists, period. Now, you might argue those radiation oncologists are causing more harm than good. That's beyond my pay grade. You might be right. But you're basically arguing for a fifth branch of oncology, which is the medical oncologist above the three that we conventionally have. I

think the immuno-oncologist is coming into his or her own right now. I don't think it's worth arguing about whether it's a genetic disease or metabolic disease. It's just a goddamn hard disease. And we need every therapy imaginable. And sometimes that will be doing things that are completely new as you've proposed. So anyway, that's on that note. I want to thank you very much for your generosity of time and just your passion for this and sort of how tirelessly you've worked on this. I mean, this is only our first time meeting today, Tom, but I've been familiar with your work for probably eight years now, which is a small fraction of the amount of time you've put into this. Dom is a very close friend. And so through Dom and through Bob, I've learned a lot more about your work.

And I know that a lot of people listening to this are going to be rooting for you to do this. who's got a loved one who's either died of GBM or has GBM, that they can do to increase the chances that either others can get the types of therapies you're talking about in clinical trials or that their loved ones themselves can? What else can they do? Well, I mean, in my position as a researcher who does the preclinical studies, I mean, we get support from Travis Foundation, the Metabolic Therapy Foundation. And that's what keeps our program going. And that's what tells us what we think should work really well or what might not work to help these people get the outcome that they want, which is high quality of life and living a lot longer. So my big thing is that. living a lot longer. So my big thing is that. We can identify those. And where do you do that?

You need funds for that. And the federal government is mostly like, what gene is involved? So this is where it comes back to the same problem again. You don't get funding for things that actually can really work versus studying the disease. Let's look at the meta. Let's study the disease more. We don't need that. We know we have a path. We have a clear path. So is there an easy path for patients who want to make financial contributions to the lab is it through a foundation that there's two ways to do it you can either do it through the foundation because we have a continual grant set up through single cost single cure foundation okay so we'll link to that to make sure that people know what that and also at boston college that like if you want to fund the work directly through the university,

it has to be through a very specific statement. Otherwise, the university will absorb some of the other funds. So basically, that's the way. Now, what we do then is our data are immediately given to the clinical people who then put it on their patients and then feed me back and say,

this is working well, or we don't think this is doing as well as we should. Why don't you tweak it in this direction? So I work with the physicians directly and I give them the preclinical information. They feed me back and see how it's working. Sometimes it works a hell of a lot better in the human than the mouse. So let's be sure that we have from you any and all means that people who are passionate about this, interested in this either personally or through sort of indirect experience can support this work. And more importantly, I think create maybe a bit of a groundswell that puts a little bit of pressure on the IRBs to say, look, this is, you know, GBM is as high stakes as it gets, right? It's the type

of cancer that gives cancer a bad name. And maybe this is one area where we have to increase our appetite for risk in clinical trials. I agree with that. And I think that this is a disease that we think we can make major advances in and why not want to give it a shot? Because it's not going to hurt anybody. It's not going to accelerate their demise. It's only going to- Well, I mean, I would disagree with that only in terms of a talking point to say it could. We don't know. But that's the point of risk, right? I mean, when the outcome is so asymmetrically bad, which is uniform death in an accelerated fashion, we have to be willing to take the risk of potentially doing worse than that. I don't think that's the case. I've never seen it. Understood. But I think the way we talk about this, when we talk about this as though there's no risk, I think that reduces our credibility with people who say, well, how can you say that?

Well, any open cranial surgery produces risk. Yeah, that's the point. And that's going to be a part of all what we're doing. Well, the point is, you know, Bob's heard me rail on this many a time. what we're doing. Well, the point is, I, you know, Bob's heard me rail on this many a time that the note, this sort of idiotic idea of a Hippocratic oath, which is technically, he didn't even say it. And it's such a dumb thing anyway, first do no harm. I mean, you, you couldn't do any good if you weren't at least willing to do some harm. No one goes into it, do it wanting to do harm. But anyway, this has been really exciting and I, and I really appreciate

your, your time and your insights and above all else, the work you've done. So thank you, Tom. Yeah, thank you. You can find all of this information and more at peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the nerd safari at peteratiamd.com. What's a nerd safari you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social, you can find me

on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk.

The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please visit peterottiamd.com forward slash about.