#30 – Thomas Seyfried, Ph.D.: Controversial discussion—cancer as a mitochondrial metabolic disease?

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [intro music]

2. 0:04 – 9:04

   Episode Preview and Guest Introduction

   1. PAPeter Attia0:04

      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 peterattiamd.com. [intro music] Hello, everyone. Welcome to this week's episode of The Peter Attia 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, 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, got that in the mid-'70s, and a bunch of other distinctions that I'm not gonna go into 'cause we're gonna link to all of 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 dis- 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 hi- 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 and how that led him to the interest in caloric restriction and ketosis. We revisit the man, the legend, Otto Warburg, and talk about the Warburg effect and Warburg's point of view on these things. And I, 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 of their views as possible. But at the same time, I hope the discussion is helpful. We get into a bunch of the semantics. I, 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 difference 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 gonna 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, 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, you'll see this in the interview. Uh, 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, my view is that cancer is about as hard a disease as there is ever going to be to, 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, 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, I think that's... 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 IV 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, 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. 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, a guy that's on the sidelines of, you know, sort of mainstream cancer. These views, these metabolic views, unfortunately, un- 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 gonna be some... I, 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 thirty or forty years are very slowly beginning to gain acceptance in-- And I don't like to use the word mainstream, but in, 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 peterattiamd.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. [upbeat music] Hey, Tom. How are you?

   2. TSThomas Seyfried8:16

      Well, thank you very much.

   3. PAPeter Attia8:18

      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, so.

   4. TSThomas Seyfried8:27

      They'll recover.

   5. PAPeter Attia8:28

      [laughs] 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 Don 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 and-- But at the same time, I think I understand cancer far less than I understand things that I didn't formally train in. Like, 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,

3. 9:04 – 19:09

   From Epilepsy and Gangliosides to Cancer Research

   1. PAPeter Attia9:04

      how did you get interested in this?

   2. TSThomas Seyfried9:06

      We started it when I was at Yale University, Department of Neurology, where we had been working on epilepsy and lipid storage diseases, the, and gangliosides basically. The complex lipid molecules. And one of the individuals that I was working with at that time, Robert Yu, he's my-- was my mentor at the time. He had done some research on ganglioside changes in tumors and, you know, we had been looking at that and I said, "You know, there were some interesting molecules in those tumor cells." So I also knew Dennis, uh, Spencer, who was the chief neuro- of neurosurgery at, 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?" And, you know, I'm, 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, and it was kind of a, an experience that I'll never forget, having someone take a, a tumor out of someone's head. And they were asking me all kinds of questions like, you know, "Do you think we should do ra- put pellets of radiation in the cavity?" And, you know, all this kind of stuff. And of course, I didn't know it. I said, "I'm here to look at the ganglioside pattern in the tumor. [laughs] I don't know how to treat the cancer or anything like this." But any event, uh, 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 nineteen thirties. And he was still alive at the time. Uh, he lived to be ninety-eight years old or something. So I, 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. Everybody's working on the glycolipids of the tumors, glycolipids of developing brain, lipid storage diseases, and epilepsy. And I wrote a grant at, internally at Yale, uh, which was rejected a-asking about ketogenic diets.

   3. PAPeter Attia11:23

      And what year was this?

   4. TSThomas Seyfried11:23

      This is back in the s- late seventies, early eighties maybe, nineteen eighty. And they said, "Oh, nobody's interested in ketogenic diets. It's kind of passé."

   5. PAPeter Attia11:33

      This was before the work at Hopkins or...?

   6. TSThomas Seyfried11:36

      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.

   7. PAPeter Attia11:44

      Mm-hmm.

   8. TSThomas Seyfried11:45

      And, and Jim was a, a, a movie director and his friend Meryl Streep made the movie, uh, 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.

   9. PAPeter Attia12:10

      But does that mean you suspected that something to do with glucose metabolism was-

   10. TSThomas Seyfried12:15

       No, nothing. I, I just thought it was an interesting a-approach to, a non-drug approach for, for seizures. And anyway, the grant was summarily rejected. It-- 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 for-- Then it was twen- ten years, fifteen years later when we developed some of the best animal models for epilepsy And, uh, we were looking at brains of biochemistry and epileptic seizures and the genes that caused epilepsy. And then one of my PhD students, Marianna 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 anyways." [laughs]

   11. PAPeter Attia12:59

       You're still traumatized by the grant.

   12. TSThomas Seyfried13:01

       Yeah, yeah. [laughs] Yeah. So I said, "They're not in... " You know, I got it summarily rejected. They, they says, "This is no- nobody interested in ketogenic diets." So anyway, I, she said, "Oh, let me..." I said... So I said I had a few extra bucks in the g- in the grant. So I said, "Okay, go on out." In fact, she wr- 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, and this guy Jim Abrams, and he's start, wants to start this foundation called the Charlie Foundation," and, 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, it was, we, 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, in the brain. Of course, uh, at that time at Boston College, animal, they didn't charge me for animals.

   13. PAPeter Attia14:03

       Hmm.

   14. TSThomas Seyfried14:03

       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, 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, to the mice, and we looked at the ganglioside. Yeah, it's really down, but so was the body weight. And then when we put the control group in, we found out that the, the, yeah, the tumors shrunk and the gangliosides were re- were, were, were reduced from this drug, but then the body weight was also reduced.

   15. PAPeter Attia14:37

       And these, the controls were also... They're both animals being fed ad lib?

   16. TSThomas Seyfried14:40

       Ad libitum. One had the drug, one didn't.

   17. PAPeter Attia14:42

       Okay.

   18. TSThomas Seyfried14:43

       And-

   19. PAPeter Attia14:43

       So the drug somehow either reduced intake or increased expenditure.

   20. TSThomas Seyfried14:46

       We don't know, but it's, the body weights were reduced by about 15 or 20%. So, 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?

   21. PAPeter Attia15:07

       Yeah.

   22. TSThomas Seyfried15:07

       So that's when they gave me $200,000 to investigate the mechanism by which their drug was stopping brain cancer, 'cause I showed them the data, and they w- they were all excited. So, uh, we then began to investigate this, and Purna Mukherjee, Dr. Mukherjee, who worked, started with me. I said, "Hey, Purna." Um, she, I hired her specifically s- to start looking at this. And then when we realized that, um, um, you know, what's, what's working, she said, "You know, a lot of times these drugs work through calorie restriction." So I said, "Well, um, 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, one was the, 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.

   23. PAPeter Attia15:49

       So they were pair-fed.

   24. TSThomas Seyfried15:50

       Pa- Wasn't pair-fed. One, uh, one group was eating ad libitum, and they were losing body weight, and the other group, uh, we-

   25. PAPeter Attia15:57

       Oh, I see. You d- Okay, I got it.

   26. TSThomas Seyfried15:58

       We had to restrict the calories-

   27. PAPeter Attia15:59

       To match their weight

   28. TSThomas Seyfried16:00

       ... to match the body weight of-

   29. PAPeter Attia16:01

       So they were, they're pair-weighted.

   30. TSThomas Seyfried16:02

       Yes.
4. 19:09 – 31:46

   Calorie Restriction, Ketosis, Fasting and Starvation

   1. PAPeter Attia19:09

      Now, if you had a... 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-

   2. TSThomas Seyfried19:22

      Yes

   3. PAPeter Attia19:22

      ... even though they would still be calorically restricted, would you get the same anti-seizure benefit?

   4. TSThomas Seyfried19:26

      Same results. Exactly. So w- 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 cal... It would be like a human doing water-only fasting.

   5. PAPeter Attia19:39

      So how, how calorically restricted did they need to be if they were not on a ketogenic diet?

   6. TSThomas Seyfried19:43

      40%. 35 to 40% restriction. And then we did some studies, 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, the ba-

   7. PAPeter Attia19:57

      Yeah, their metabolism is-

   8. TSThomas Seyfried19:58

      Right, is seven or eight times higher than that of a man. So humans can achieve much higher ketosis than a mouse can. And the mouse, so one week, a, 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.

   9. PAPeter Attia20:13

      IRBs don't allow you to fast mice that long anymore, do they?

   10. TSThomas Seyfried20:16

       Oh, yeah. I mean, as long as they, as long as they're healthy, you know. Calorie restriction is generally a healthy thing. If you... You don't wanna over-restrict, because then you're put into a nutritional imbalance, and you don't wanna go to the level of what we call starvation. Uh, 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 a, uh, that's very pathological. You don't ever wanna go to that digression. So some people that like, they, they get so carried away with, with water-only fasting, they can enter into starvation mode. And I know this for a fact because I used to spend a lot of time with George Cahill-

   11. PAPeter Attia20:55

       Mm-hmm

   12. TSThomas Seyfried20:55

       ... who used to run the Joslin Diabetes Centers down here in Boston. And he and I would talk for hours and hours with Bud Veatch at the NIH about how long people can go with this, uh, transition over from therapeutic fasting into starvation. And also the body builds, it's like anything. Your body gets accustomed. Uh, you can go a long time without eating if you're, if you're in shape, you know, if you've done this. But, you know, it depends on what your body weight is, what your, how old you are. It depends on a lot of different things, how long you can go without eating. But, you know, the bottom line is that you w- we were trying to d- develop a therapy and, and figure out the mechanisms by which ketogenic diets were therapeutic.

   13. PAPeter Attia21:33

       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 are there, were there general rules about once you cross over that point where you're basically, you know, pulling nitrogen out of the muscle?

   14. TSThomas Seyfried21:56

       Right. Right. And, and, and he got that, those data actually from the, the 10 guys that starved to death in Maze, Maze Prison in Eng- in, uh, northern Ireland. Bobby Sands in that group, actually. He was there monitoring their blood work while they were dying of starvation.

   15. PAPeter Attia22:10

       These, these, these were prisoners that, they were fasting, uh, as a protest.

   16. TSThomas Seyfried22:14

       Yes.

   17. PAPeter Attia22:14

       Correct?

   18. TSThomas Seyfried22:14

       Yes.

   19. PAPeter Attia22:14

       Yeah.

   20. TSThomas Seyfried22:15

       Um, they made a movie out of it, Every Mother's Son, about the, th- there was 10 Irishmen that were, uh-

   21. PAPeter Attia22:20

       How long did they live on average?

   22. TSThomas Seyfried22:21

       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, the, the, it was very interesting. It's a horrible thing. It's like one of the worst ways to die is, is starvation. So what happens, your diaphragm is the last muscle that would be digested, and there's a, there's a momentum that starts. Now, you have to realize that these guys that did this were-

   23. PAPeter Attia22:48

       Oh, so they don't die of just acidosis.

   24. TSThomas Seyfried22:50

       No.

   25. PAPeter Attia22:50

       There's the... It's actually the diaphragm.

   26. TSThomas Seyfried22:52

       You drown. They're drowned in your own body fluids.

   27. PAPeter Attia22:54

       Oh, God.

   28. TSThomas Seyfried22:54

       Basically. Geez, it's brutal. So, um, because what happens is once your diaphragm can't work, your lungs fill up with, with fluids, and you drown in your own fluids.

   29. PAPeter Attia23:04

       And the diaphragm presumably stops working because of either the loss of muscle or the electrolyte imbalance that-

   30. TSThomas Seyfried23:09

       Yeah, both. A combination of both. So, uh, and then there's a mo- you can't stop it. Y- Once, once the momentum starts-
5. 31:46 – 42:09

   The Warburg Effect and Defective Respiration

   1. PAPeter Attia31:46

      So let's back up for a moment for, for people. I mean, I think most people listening probably know what the Warburg effect is and, and, and who Warburg was, but maybe just give us a moment of setting the stage for what he, what his observation was that now bears his name.

   2. TSThomas Seyfried31:59

      Well, his interest was in biochemistry. Uh, he was a classical chemist, biochemist in his, in his time. And, uh, he began to look at the metabolism of tumors. So he made a, an observation which was solidified that cancer cells continued to do a ancient fermentation metabolism even in the presence of oxygen. So this, the Pasteur effect from Louis Pasteur with the yeast was that, you know, yeast will ferment. They evolve. That organism evolved to be able to ferment, get energy in the absence of oxygen. But when as soon as oxygen came into the, 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, 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, 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 Past- the Pasteur effect wasn't working.

   3. PAPeter Attia33:14

      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.

   4. TSThomas Seyfried33:22

      Right.

   5. PAPeter Attia33:22

      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.

   6. TSThomas Seyfried33:36

      Mm-hmm.

   7. PAPeter Attia33:37

      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 you, 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 thirty units of ATP.

   8. TSThomas Seyfried34:01

      Right.

   9. PAPeter Attia34:02

      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."

   10. TSThomas Seyfried34:13

       Right, and that's what he finds when you take normal tissue like kidney slices or muscle slices or, or liver. You grow them in %100 oxygen and they produce minimal to barely detectable lactate. There's always some going to be produced in every tissue, but basically it's, 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, a phenome- and 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, if pyruv-- Now that's the Embden-Meyerhof pathway going from, from glucose to pyruvate. Pyruvate is the end of the Meyer- is the end of that. So then the opportunity is that the pyruvate would enter into the mito- under oxygenated conditions and be fully oxidized to water and CO2. And oxygen is the acceptor of the electrons to form the, 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.

   11. PAPeter Attia35:37

       Let's just clarify that. Many people when they hear that will assume-- We, they, we think respiratory system, we think of lungs. What you really mean is the mitochondrial-

   12. TSThomas Seyfried35:44

       Right, right

   13. PAPeter Attia35:45

       ... machinery that undergoes what we call cellular respiration.

   14. TSThomas Seyfried35:48

       The lungs are bringing in the oxygen.

   15. PAPeter Attia35:50

       The oxygen and getting rid of the CO2-

   16. TSThomas Seyfried35:52

       Right

   17. PAPeter Attia35:52

       ... that enables mitochondria.

   18. TSThomas Seyfried35:53

       That enables all the cells in our, majority of our cells in the body to, 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, get the good air in and the bad air out. And 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, noti-noticing that there were some defects in, in these kinds of things. Um, but he wasn't at the level of electron microscopy or this... He just made the-

   19. PAPeter Attia36:40

       What year? This is in the 1920s or 1930s?

   20. TSThomas Seyfried36:42

       Uh, ear- uh, mostly late '20s, '30s, '40s, all the way up to the '50. I think he stopped his research maybe in the early '60s.

   21. PAPeter Attia36:49

       Now, he won a Nobel Prize, didn't he?

   22. TSThomas Seyfried36:51

       Yeah. He, he-

   23. PAPeter Attia36:52

       Was it for the description of this phenomenon?

   24. TSThomas Seyfried36:53

       No, it was for the discovery of cytochrome c oxidase-

   25. PAPeter Attia36:56

       Hmm

   26. TSThomas Seyfried36:56

       ... which is actually one of the key enzymes in the electron transport chain, how cells generate energy through respiration. So he, he, 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. Um, and he had very strong ideas and very excellent quantitative measurements, uh, 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 s- the cells are producing all this lactic acid? Because the organelle that is sup- is supposed to be involved is defective. This led to a lot of controversy. What do you mean defect? How defective? What do you mean? So much later, Pete Peterson from Johns Hopkins had done a m- a, 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, 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 a-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, that you're taking cells from a tissue and separating them and growing them as, 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.

   27. PAPeter Attia39:20

       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, if you're not in cell culture, how do you quantify the amount of aerobic respiration?

   28. TSThomas Seyfried39:41

       You look at the amount of oxygen consumed-

   29. PAPeter Attia39:43

       Mm-hmm

   30. TSThomas Seyfried39:43

       ... and the amount of lactic acid produced. So if you're doing aerobic respiration, you're consuming a lot of lactic acid, uh, 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, seven ATP units to nine, depending on the system, but it's, you know, Warburg used the word, the, 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.
6. 42:09 – 49:55

   Genes, Mitochondria, Viruses and Cancer Origins

   1. TSThomas Seyfried42:09

      Oh, I wouldn't call them mutations. They would call them defects. Now, you can have a mutant-

   2. PAPeter Attia42:12

      In other words, the genome is unaffected in some of those cases?

   3. TSThomas Seyfried42:15

      Yes. We, we've done, we've done that. We sequenced the entire genome of, of five different independently derived cancers from mouse, all der- all derived from different origins, and we didn't find a single genetic abnormality, patho-- what we call pathogenic, where, where you, where the mutation would actually have a, of, of a, have an effect on a function, and we didn't find a single one. So that, that whole-

   4. PAPeter Attia42:35

      So let's take, maybe take a step back and, and, uh, 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 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.

   5. TSThomas Seyfried43:02

      Well, they say it's about five to six percent.

   6. PAPeter Attia43:05

      Oh, it's that high? Okay.

   7. TSThomas Seyfried43:06

      You know, and you hear about them, the BRCA1-

   8. PAPeter Attia43:08

      Yeah, yeah. Of course

   9. TSThomas Seyfried43:08

      ... BRCA2, p- Li-Fraumeni, p53, you know.

   10. PAPeter Attia43:12

       Lynch syndrome, etc.

   11. TSThomas Seyfried43:13

       Yeah, yeah. But when we looked into those so-called inherited risk-- We call them inherited risk factors. None of them have ever been one hundred percent penetrant, which means that e- every person having that gene must express-

   12. PAPeter Attia43:24

       They're not purely deterministic.

   13. TSThomas Seyfried43:26

       Yeah, they're not deterministic. And as Warburg said, there are many secondary causes of cancer, but there's only one primary cause, and the primary cause is the damage to the, to the respiratory system. So if the inherited mutation damages the respiratory system of the cell, the probability of cancer is, is a real possibility. So because everybody who has Li-Fraumeni 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 get the ca-- they never develop a tumor because for whatever reason, in that person, that mutation did not damage the respiration. That could be a, um, an environmental suppressive effect or another gene in the, 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, uh, 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.

   14. PAPeter Attia45:12

       Because the Warburg effect was largely forgotten for many years after his initial observation, right?

   15. TSThomas Seyfried45:17

       Yeah. A lot of what he did was forgotten, and Pete Peterson was one of the few guys that kept the fire burning in-- Because a lot of the-- Because as, as I said, when Watson and Crick discovered the DNA, uh, 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 b- 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, 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, uh, more and more genetic defects, and all these kinds of things, leading people to believe that these were the causes of the disease. And, you know, a lot of, uh, really nice experiments were done where they would introduce, you know, mutant virus particles into cells, and they would integrate into the nuclear genome, and then you'd see the cancer cells, ca- cells lose, become transformed into a neoplastic kind of a cell, making, giving the appearance that this was a cause effect, that if I... 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 as a-

   16. PAPeter Attia46:32

       But if the viruses are doing that, presumably they're integrating into the genome?

   17. TSThomas Seyfried46:36

       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, a protein product that then, then disrupts-

   18. PAPeter Attia46:52

       Mm-hmm

   19. TSThomas Seyfried46:52

       ... the, the mitochondria. Either way, the mitochondria are disrupted, whether it, uh, uh, 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, and disrupts the organelle, and this is what we're finding for, for the majority of, of these situations. So even the inherited mutations that we look at, uh, they disrupt mitochondrial function, and if they disrupt mitochondrial function, you're at risk for developing a neoplasm in that particular population of cells.

   20. PAPeter Attia47:20

       There are some cancers that don't follow that, correct? I mean, aren't there some cancers that have normal mitochondria?

   21. TSThomas Seyfried47:27

       We haven't found any because the, the, the evidence for that is that they're ev- 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, if its respiration would be normal, uh, it shouldn't be fermenting. As a matter of fact, Dean Burk did this kind of a study way back in the '50s. He went and looked at hep, various kinds of hepatomas because they, there was an article that was published to say that there was this very low, slow-growing hepatoma that did not ferment, so which was directly related to your question. But Burk, 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, uh, lactic acid. Another, another, 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 d- damaged respiration, [laughs] they were fermenting just like the, just like the mouse tumors.

   22. PAPeter Attia48:42

       When you say respiration, you mean photosynthetic respiration?

   23. TSThomas Seyfried48:45

       No, no, plants have both. Plants can get energy from chloroplasts-

   24. PAPeter Attia48:49

       Mm-hmm

   25. TSThomas Seyfried48:49

       ... to build carbohydrates, but they also have, they also have mitochondria.

   26. PAPeter Attia48:52

       Oh, I didn't realize that. So their carbon fixation obviously comes from photosynthesis.

   27. TSThomas Seyfried48:56

       Yeah, yeah.

   28. PAPeter Attia48:57

       But when they make, you know, their, their equivalent of starch-

   29. TSThomas Seyfried49:00

       Yes

   30. PAPeter Attia49:00

       ... kind of effect, then-
7. 49:55 – 56:39

   Building Blocks, Glutamine and Substrate-Level Phosphorylation

   1. PAPeter Attia49:55

      So before we get to that, 'cause I, 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, uh, cell mate 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 Vander Heiden and, I think, uh, Lou Cantley and Craig Thompson wrote that paper in 2009 that is, uh, I'm sure you're familiar with. It was a science paper, I believe. And they proposed this other explanation, which was, "Look, it's an, it's, it's not, 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?

   2. TSThomas Seyfried50:45

      Yeah, of... Well, you know, y- in the process of, of upregulating the Embden-Meyerhof pathway, you are gonna get the carbons to, 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. Now, this... But they're, they deviate from the path, from Warburg's theory in saying that respiration is normal, okay? They, they think there's nothing wrong with the mitochondria, okay? They've said that many times. Craig Thompson has said this, that I, I can't... 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, which is a life's work showing that the mitochondria have no... Yeah, but he doesn't mention that, and, and they don't t- discuss Pete Peterson's massive amount of evidence. But you're right. To, 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, and the glycolytic pathway, and it's also coming from glutamine. So these cancer cells are sucking down glutamine. So you're, 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 is 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 Tschanapolis in, in Hungary, I, I proposed this a long time ago on, on a purely theoretical basis, having been convinced that Warburg was right, that the respiration of c- all cancer cells is damaged to some extent. So we're... 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 F- in Warburg's basic theory.

   3. PAPeter Attia52:44

      So explain what, uh, SLP is.

   4. TSThomas Seyfried52:46

      Substrate-level phosphorylation is the production of, of ATP when you move a phosphate group from an organic substrate onto an ADP molecule. So it's a ancient way of generating energy. In other words, it's an organic molecule that's an electron acceptor rather than oxygen.

   5. PAPeter Attia53:03

      Right. So instead of going through the electron transport chain where you use NAD, NADH, NADP, NADPH as electron transporters-

   6. TSThomas Seyfried53:11

      Well, electron donors

   7. PAPeter Attia53:12

      ... electron donors-

   8. TSThomas Seyfried53:13

      Yeah

   9. PAPeter Attia53:14

      ... 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.

   10. TSThomas Seyfried53:25

       Well, you... For substrate-level phosphorylation.

   11. PAPeter Attia53:27

       Yes, yes.

   12. TSThomas Seyfried53:27

       Yeah, so, so succinyl-CoA, uh, has a phosphate group on a serine inside the, the protein itself, and that phosphate group is then donated to A- ADP, and sometimes GDP, G- 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, onto the, onto the ADP as, 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.

   13. PAPeter Attia53:57

       And does that occur inside the mitochondria, inside the inner-

   14. TSThomas Seyfried54:00

       Yes, yes

   15. PAPeter Attia54:00

       ... inner matrix?

   16. TSThomas Seyfried54:01

       Yeah, it's in the matrix.

   17. PAPeter Attia54:02

       Uh-huh.

   18. TSThomas Seyfried54:02

       So you're gonna be blowing out a lot of... You're gonna make a lot of AT... It's gonna 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.

   19. PAPeter Attia54:16

       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?

   20. TSThomas Seyfried54:29

       Well, we do. In the heart muscles, they do. They've, they... On various cardiac, uh, in restrictions and things like that. A lot of this has been worked out in the heart, so it does happen. I mean, the, 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 under normal conditions with substrate-level phosphor- You hold your breath, you're gonna be able to survive for a certain period of time. Lactic acid builds up. I mean, this was shown by, um, Hochachka when he did some incredibly interesting experiments trying to hold various aquatic animals underwater and, and looking at the metabolic changes that occurred. So seals, porpoises, turtles, you know, 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 for... 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, the bottom line is he started measuring all these metabolites in the bloodstream. Lactic acid goes right through the massive amount. I'd expect that, right? So, and succinic acid. Succinic acid is another... So succinate, succinic acid is part of the, uh, in the electron tr- in the TCA cycle, is a powerful stimulatory towards oxidative phosphorylation, and it was being dumped out into the, into the circulation. So, um, it wasn't being oxidized. So, so he claimed that it was amino acid fermentation that was doing this. So the body was grabbing amino acids and, and, and metabolizing them and, 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 ox phos. So you look at cancer cells, and they're dumping out succinic acid, and succinic acid, it, it stabilizes HIF-1 alpha, so you can continue to up the transcription factors for driving fermentation. So this whole thing is just a, is just a massive shift from ox phos to substrate-level phosphorylation.

   21. PAPeter Attia56:27

       Does creatine phosphate fit into that SLP pathway, or is that totally separate?

   22. TSThomas Seyfried56:31

       Uh, I'm not sure about that. It could be a source of the phosphate groups, but I haven't looked into that. Dom- Dominic may, may know a lot more about that than I do.

8. 56:39 – 1:04:11

   Why the Field Disagrees: Oxygen Uptake and Uncoupling

   1. PAPeter Attia56:39

      So when you go back to sort of... There's a, 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.

   2. TSThomas Seyfried56:49

      Just, it's only, it, it's just a matter of time, okay?

   3. PAPeter Attia56:52

      Why do you think that is? What do you think is the... I mean, uh, 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, I, I find those things hard to believe.

   4. TSThomas Seyfried57:10

      Yeah.

   5. PAPeter Attia57:10

      Do you think there's a, a, a, a better explanation for why these hypotheses are not being investigated with the rigor that maybe they should be?

   6. TSThomas Seyfried57:19

      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 ex- 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, and not looking at the actual consumption of oxygen and lac- production of lactic acid, not looking at what Warburg actually looked at, then you have a d- a very different explanation for, for what's happening. So a lot of people today look at, 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 will take, 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 exper-

   7. PAPeter Attia58:28

      How, how would one measure that? ATP is very tricky to measure, ATP production.

   8. TSThomas Seyfried58:32

      No, ATP can be measured. The pro- the problem is, is that what's the origin of it? The, the, and of the-

   9. PAPeter Attia58:37

      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-

   10. TSThomas Seyfried58:44

       Right

   11. PAPeter Attia58:44

       ... as measured by, you know, 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?

   12. TSThomas Seyfried58:55

       Well, if it's taking up oxygen, well, it, it, it, if it doesn't make ATP, it's dead, all right? So-

   13. PAPeter Attia59:01

       Uh, sorry, if it's, if it's not making ATP commensurate with its oxygen consumption.

   14. TSThomas Seyfried59:06

       Well, sometimes you look at that and you'd say, "Wow, look at the oxygen consumption is... The, the ATP production is commensurate with oxygen uptake."

   15. PAPeter Attia59:12

       Yes.

   16. TSThomas Seyfried59:13

       Okay. So-

   17. PAPeter Attia59:14

       That would be coupled, wouldn't it?

   18. TSThomas Seyfried59:15

       As long as it's not producing lactic acid or succinic acid, okay?

   19. PAPeter Attia59:19

       Well, so I, 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?

   20. TSThomas Seyfried59:35

       That's an important point because a lot of people stumble on that. The, 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, where the oxygen is in fact linked to the ATP through F1, F0 ATPase, or whether it's coming from mitochondrial substrate-level phosphorylation.

   21. PAPeter Attia1:00:01

       Ah, got it.

   22. TSThomas Seyfried1:00:02

       Inside, inside-

   23. PAPeter Attia1:00:02

       So you can't, there's no, 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.

   24. TSThomas Seyfried1:00:13

       Well, well, Warburg did that, but he was looking at-

   25. PAPeter Attia1:00:16

       But he didn't know about SLP, right?

   26. TSThomas Seyfried1:00:17

       Uh, he... Well, lactic acid production, the production of ATP at the pyruvate kinase is substrate-level phosphorylation, but it's cytoplasmic.

   27. PAPeter Attia1:00:26

       Yes, yes. It's not mitochondrial.

   28. TSThomas Seyfried1:00:27

       It's not mito- not mitochondrial. He did not know. He couldn't have known because the very systems that were, the, the, 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, what people have failed to realize is that the, they, they consider... Every, 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, 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. Makes a buttload of lactic acid, but it's not making-- it's not linked to the ATP production. So therefore, they have to say n- respiration is normal because the cell is making so much ATP. But if Otto Warburg is correct and, and all of the b- all of the structural biochemistry is correct, the mitochondria can't be making oxygen from oxidative phos-- it can't be making ATP from ox phos. 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, it sh-- and glutamine is being consumed in massive amounts, so it's gotta be coming from substrate-level phosphorylation.

   29. PAPeter Attia1:01:58

       What is the fundamental structural defect in the mitochondria? Which is interesting. I'd, 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-

   30. TSThomas Seyfried1:02:17

       Yes
9. 1:04:11 – 1:18:54

   Starving Tumors: Glucose Limits, Ketones, Insulin and Glutamine

   1. PAPeter Attia1:04:11

      Now, one can't render glucose zero, meaning th- 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?

   2. TSThomas Seyfried1:04:25

      So let, let me, let me just-- 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.

   3. PAPeter Attia1:04:39

      Sure, and they've got to below one millimolar.

   4. TSThomas Seyfried1:04:41

      Yeah, .5.

   5. PAPeter Attia1:04:42

      Yeah.

   6. TSThomas Seyfried1:04:42

      Point [laughs] So.

   7. PAPeter Attia1:04:43

      But, but sustainably, it's very difficult to be below about three millimolar, right?

   8. TSThomas Seyfried1:04:47

      Right. Right. But, 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. 'Cause 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 ke- 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.

   9. PAPeter Attia1:05:37

      It's interesting 'cause 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 the, obviously the dominant sink for glucose-

   10. TSThomas Seyfried1:06:13

       Right

   11. PAPeter Attia1:06:13

       ... basically become resistant to insulin, uh, not in a pathologic way, but rather in a way to allow the brain to have access for the remaining glucose.

   12. TSThomas Seyfried1:06:22

       Well, if you do it in acute systems like that, rather than the chronic changes that we're, that we talk about, you can get those kinds of, get, get those kinds of an effect. Generally, calorie restriction makes the body super insulin sensitive.

   13. PAPeter Attia1:06:34

       Yeah. It's interesting. I, uh, this is something I've struggled with because, uh, you know, I was on a ketogenic diet for three years, and at the end of that period of time, I, um, went up to Stanford and did, um, an insulin suppression test, which is, along with the euglycemic clamp, really the gold standard for measuring, measuring insulin sensitivity with Gerald Reaven, the late Gerald Reaven. And Jerry was just interested in my physiology. It was like, "Wow, you're kind of a weird guy. You, 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 a 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. So, 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-

   14. TSThomas Seyfried1:07:58

       Well, let me, let me... Why, why would you, uh, 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 physiologic. So you're actually giving too much insulin in a situation like that.

   15. PAPeter Attia1:08:12

       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.

   16. TSThomas Seyfried1:08:19

       Yeah, yeah.

   17. PAPeter Attia1:08:19

       These are all people eating a standard diet. But what you've, what you're alluding to is what we discovered very quickly. So again, this is supposed to be a six-hour test.

   18. TSThomas Seyfried1:08:27

       Yeah.

   19. PAPeter Attia1:08:27

       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, perfectly reasonable, and the highest was, I, I w- I don't recall this, but, uh, 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 2 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 gonna back off on the insulin," to your point. At 90 minutes, and I have to go back and look 'cause I have all the data. I, I could be wrong. Maybe it was a little longer than that, but 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 gonna stop the test now because your, your glucose is in the 40s." I believe I was at about 48.

   20. TSThomas Seyfried1:10:07

       Yeah, no ketones. You're gonna go unconscious. You gotta be careful.

   21. PAPeter Attia1:10:09

       Yeah. So in the end, I almost did go unconscious, and the last thing I sort of remember was [laughs] the profound perspiration that came over me, which is very different from the perspiration you experience, like, on a day like today in Boston, where it's hot and you're sweaty. It's, it's not that type of a perspiration at all. It felt like I was in a shower.

   22. TSThomas Seyfried1:10:29

       Yeah.

   23. PAPeter Attia1:10:30

       And I began shaking and probably was about to have a seizure, and then they went... So the last blood glucose I think they, I, they got on me was about 31 milligrams per deciliter, and when they were injecting n- 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 vein.

   24. TSThomas Seyfried1:10:56

       Why, why, why, why you put yourself in these situations?

   25. PAPeter Attia1:10:57

       Yeah, I know. I'm an idiot. I mean, I-

   26. TSThomas Seyfried1:10:58

       [laughs]

   27. PAPeter Attia1:10:59

       The worst part of that story is I did-

   28. TSThomas Seyfried1:11:00

       I would never do, I would never do any of that stuff [laughs] .

   29. PAPeter Attia1:11:02

       No, no. When I came back to life-

   30. TSThomas Seyfried1:11:03

       [laughs]
10. 1:18:54 – 1:33:41

    Testing the Hypothesis: Structure, Function and Cell Types

    1. PAPeter Attia1:18:54

       So before we get into the therapeutic stuff, which I understand is probably what everybody wants to hear about, I, I still wanna 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?

    2. TSThomas Seyfried1:19:31

       Well, I, 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?

    3. PAPeter Attia1:19:42

       Mm-hmm.

    4. TSThomas Seyfried1:19:42

       The bottom line is where are they getting their energy from? If you stop their energy-

    5. PAPeter Attia1:19:46

       The, the board picture, by the way, we're looking at everything. We're looking at the... Uh, 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.

    6. TSThomas Seyfried1:20:00

       Yeah, the, it's, 'cause 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, I break it down into s- 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. That's, in my mind, that is a solid fact, and to deny that, one would have to ignore the evidence that I've looked at. Uh, 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 white black and black white. I mean, y-

    7. PAPeter Attia1:20:46

       But, 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?

    8. TSThomas Seyfried1:20:56

       Well, as I said-

    9. PAPeter Attia1:20:57

       Experimentally, I mean.

    10. TSThomas Seyfried1:20:57

        Yeah, of course, and we do, and we do that. So we know structure dictates function. We, well, that's, uh, 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 met proteins in the electron transport chain?

    11. PAPeter Attia1:21:14

        And, and just as an... 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 q- quantify structure as, you know, a scale from one to 10, and obviously a, a, a 10 out of 10 structure is perfectly functional. You'd wanna believe that that thing would function good enough down to, like, a two out of 10, and only if you are staggeringly compromised does everything go to hell. So in other words, uh, just to push back for a moment, one could argue, "Hey, yeah, of course there's structural changes, but they're, they're not functionally relevant because they're within a parameter space that-"

    12. TSThomas Seyfried1:22:12

        Yeah. No, that's an important point, and I think the normal flexibility of our cells-

    13. PAPeter Attia1:22:16

        Yeah, that's the better word.

    14. TSThomas Seyfried1:22:17

        Yeah, yeah.

    15. PAPeter Attia1:22:17

        It's the flexibility.

    16. TSThomas Seyfried1:22:17

        Yeah, the normal flexibility is able to accommodate those kinds of changes over the short period of time. Mitochondria is such a, an incredibly vibrant system. It's a, it's a living organelle inside of our cells.

    17. PAPeter Attia1:22:29

        Right.

    18. TSThomas Seyfried1:22:29

        Right? It's a, it's a, it's a, a separate organism, actually.

    19. PAPeter Attia1:22:31

        Separate DNA.

    20. TSThomas Seyfried1:22:32

        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 f- the life of the cell. And so it, it... Why should I do this activity when I can get a dumbass nucleus to do it for me? But I'm still gonna hold the keys to the kingdom. There's still 13 genes that if anything goes wrong with them, you're dead.

    21. PAPeter Attia1:22:55

        Yeah.

    22. TSThomas Seyfried1:22:56

        And this is the whole thing, why cancer cells don't die through the apoptotic mechanism, because the very organelle that controls the, the kill switch is d- [laughs] Doesn't, the switch doesn't work. So the cell bypasses the normal s- 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 un- 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. This is Szent-Györgyi, Albert Szent-Györgyi. It was alpha period in the existence of the planet. So everything was working on substrate-level phosphorylation. It was no oxidative phosphorylation. They were 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 v- various physi- physiological stress s- stress situations. They're not a perm-- 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 never, 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 'cause usually 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 gonna die.

    23. PAPeter Attia1:24:30

        But wait, wouldn't skeletal muscle be one of the highest candidates to be able to upregulate fermentation given their ATP demand?

    24. TSThomas Seyfried1:24:37

        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. They, the muscles will die on you. The cells will die if you try to force them into a fermenta- long-term fermentation metabolism. But they have the capacity to upreg- fer- 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.

    25. PAPeter Attia1:25:04

        But let, let's go back to the... This is an interesting point you bring up. Let's go back to a myocyte within my Quadricep

    26. TSThomas Seyfried1:25:12

        Yeah

    27. PAPeter Attia1:25:12

        Versus a epithelial cell in my colon.

    28. TSThomas Seyfried1:25:16

        Yeah.

    29. PAPeter Attia1:25:16

        To your point, the probability I will get a cancer that arrive, that comes from the myocyte in my quadricep is virtually zero.

    30. TSThomas Seyfried1:25:23

        No, I didn't say virtually zero.
11. 1:33:41 – 1:39:37

    Lactate Transport, Avastin and the Tumor Microenvironment

    1. PAPeter Attia1:33:41

       How much of that lactate is leaving the cell and going back to the liver to-

    2. TSThomas Seyfried1:33:45

       Yeah

    3. PAPeter Attia1:33:45

       ... undergo the Cori cycle?

    4. TSThomas Seyfried1:33:46

       Yes, a lot of it. A lot of it does.

    5. PAPeter Attia1:33:48

       Has anyone ever looked at patients who have a very, very high tumor burden and seen if they appreciably have higher serum lactate levels?

    6. TSThomas Seyfried1:33:55

       Yes. The blood cancers have been done. The, fun- some of the-- so in fact, some-- 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, okay? So the leukemia, the same thing. It's a blood cell. They're mitochondria defective, so they're throwing out a lot of lactic acid.

    7. PAPeter Attia1:34:17

       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 cell, right? White, white blood cells could actually cause capillary damage, and you, you-- that, that lactic acidosis could actually be from other organs.

    8. TSThomas Seyfried1:34:36

       That's true. And the paper that I read seemed to focus on the lactic acidosis from the cancer cells themselves, but that doesn't rule out the-- what you just said.

    9. PAPeter Attia1:34:44

       Yeah. And we-- I don't know how you'd quantify the distinction between them.

    10. TSThomas Seyfried1:34:46

        You know, it's another one of these things. But, but the question is, you know... But you're right. You can't me- like a solid tumor, um, seeing a lot of lactic acid in the bloodstream, it, it go- the Cori cycle clears it out pretty quick. So you're gonna be taking that lactic acid and making glucose again from it, which then goes back to the-

    11. PAPeter Attia1:35:04

        Do, do tumor cells upregulate the machinery? I believe MCT2 is the lactate transporter.

    12. TSThomas Seyfried1:35:09

        Yeah.

    13. PAPeter Attia1:35:10

        Do they upregulate that specifically?

    14. TSThomas Seyfried1:35:12

        Yeah. That's-- I mean, it's, it's upregulated, and so is lactic acid, LDHA, lactic acid dehydrogenase A, which converts pyruvate to lactic acid-

    15. PAPeter Attia1:35:22

        Oh, yeah

    16. TSThomas Seyfried1:35:22

        ... rather than B.

    17. PAPeter Attia1:35:24

        Yeah.

    18. TSThomas Seyfried1:35:24

        See, most cancer cells do not have elevated levels. This is why some people say, "Oh, cancer cells can burn lactic acid." Oh, where, where are they burning it? Oh, well, because, you know, they're taking it back in. The cancer cells are burning. No, that's bullshit. If it can't put py- 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, it-- and it's gonna go up to-- you're gonna store it as glycogen. Glycol-- You're gonna... It's not gonna be respired. It's gonna-

    19. PAPeter Attia1:35:48

        But do you know if anybody's looked at that and seen if MCT2-- I think it's MCT2 is the transporter.

    20. TSThomas Seyfried1:35:52

        Yeah, they're upregulated. They're upregulated.

    21. PAPeter Attia1:35:52

        It should be upregulated a lot.

    22. TSThomas Seyfried1:35:53

        Yeah, they're up-- yeah, they're upregulated. There, there's no question they're upregulated.

    23. PAPeter Attia1:35:57

        Because otherwise, the hydrogen ion would poison the cell.

    24. TSThomas Seyfried1:36:00

        Yeah. So you have the whole thing is upregulated, m- monocarboxylic acid transporters. They dump out, and they also take in ketones. Don't forget, the same, that same transporter brings in ketones. So when you go into ketogenic diets, the MCTs are upregulated as well. So y- you're bringing in more t- more ketone bodies now to replace those-

    25. PAPeter Attia1:36:17

        So that, there's an irony for you, right? They're the same-- the thing that you use to bring in ketones is cause-- is giving you the exit for lactate, which protects the cell from the harm of the acidosis that comes with the hydrogen ion.

    26. TSThomas Seyfried1:36:28

        In, in the microenvironment of the tumor, it's a real, 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, the local bloodstream and get back to the liver that way. But otherwise, it's gonna be a, a, a real acidic mess, which then, which then contributes further to the fermentation behavior of the cells, which then they're, they're resistant, so they're, they're fermenting, right? So they don't need blood, blood vessels. Uh, so this is the whole why the angiogenic a- 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, it doesn't need the blood vessels. It can ferment.

    27. PAPeter Attia1:37:09

        Did you know Judah Folkman, by the way? You guys were basically neighbors here.

    28. TSThomas Seyfried1:37:12

        Yeah. Yeah, I know he came down here, gave a talk. You know, some of his-- he ta- he targeted some unusual kinds of cancers with this anti-angiogenic. But, uh, uh, Napoleon Ferrara, 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 te- 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-

    29. PAPeter Attia1:37:40

        They still use it. Do they still use it for colon cancer as well?

    30. TSThomas Seyfried1:37:42

        I don't know of colon cancer, but for- certainly for, for brain cancer. So what are you doing? You're targeting the blood vessels a- and then forcing these cells to spread throughout your whole brain.
12. 1:39:37 – 1:49:17

    Macrophage Fusion and the Origin of Metastasis

    1. PAPeter Attia1:39:37

       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 themself may be responsible for actual metastatic behavior.

    2. TSThomas Seyfried1:39:52

       Yes.

    3. PAPeter Attia1:39:53

       Can you say a bit more about that?

    4. TSThomas Seyfried1:39:54

       Well, this is a concept that what goes all the way back to Achille from 1906 in Germany, where he was a- a- able to show that, um, in colon, I believe it was colon or m- melanoma, I can't remember the t- tissue. He was actually observing fusion be- behavior between the neoplastic cells and the, uh, cells of our immune system, and then claimed that he thinks after this fusion, fusion event that these cells become much more aggressive and much more dispersive than, than before these fusion events. This was then solidified by the work of John Paolic at Yale University, where he did some beautiful experiments showing that malignant melanoma is actually a macrophage disease. They're the resulting of fusion hybridization. This was then further established by Melissa Wong and her group at, at the Portland Medical Center there, um, the health, health science center in, in Portland, Oregon. Beautiful work showing, showing how in the colon, how macrophages were fueling with ne- fusing with neoplastic stem cells, forming these hybrid cells. So the question... And we know that all these metastatic cancers are highly fermentative, all right? We know that's a fact. They're all, they're all highly fermentative. So, and they're all very, very invasive, and they spread. They, they m- migrate through the, the blood-brain bar- they migrate everywhere. They just invade. And these are all behaviors of macrophages.

    5. PAPeter Attia1:41:09

       When you say fusion, so you have a neoplastic cell-

    6. TSThomas Seyfried1:41:13

       Yeah

    7. PAPeter Attia1:41:14

       ... that is above the basement membrane-

    8. TSThomas Seyfried1:41:16

       Got it

    9. PAPeter Attia1:41:16

       ... and you have a m- a macrophage, and tell, tell me what the fusion actually is. Are they fusing genetic material, or are they just fusing cytoplasmic material? What's actually happening?

    10. TSThomas Seyfried1:41:26

        Well, it's, it's a combination of both, actually. So macrophages, cells of our immune system, are extres- extremely fusogenic, okay? They do this to f- 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. In 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 f- 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, 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 because-

    11. PAPeter Attia1:42:44

        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.

    12. TSThomas Seyfried1:42:52

        No, but it creates a... It throws out lactic acid and creates a kind of a hypoxic micro area, okay? A micro area of hypoxic, because the lactic acid is a signal of hypoxia. It's a signal of some sort of damage. Uh, uh, you're not supposed to have pockets of Build up lactic acid in parts of your body. So it sends o- and, and normally this, if this does happen, if we have a contusion or a cut, cells of our im- the monocytes m- mass migrate out of the bloodstream, go into the wound, clear up the debris, kill the bacteria, and then move out of that, out of that section, go back to local lymph nodes and sit there-

    13. PAPeter Attia1:43:27

        Right, right

    14. TSThomas Seyfried1:43:27

        ... in the event that they're needed again, or if they're pus, they form pus. They, 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 in that if you have a colon lesion or a breast lesion from an occluded milk duct or whatever, or a lesion in the colon, you have population of cells that will start to proliferate, creating a damage to the local microenvironment, signaling a system this, the, our immune, [whistles] there's something going on here.

    15. PAPeter Attia1:43:52

        Right. So when the macro- when the monocyte gets out and differentiates, become the macrophage, goes to this now poorly differentiated cell, why doesn't it just kill that cell non-specifically? 'Cause this is just a macrophage.

    16. TSThomas Seyfried1:44:05

        Right.

    17. PAPeter Attia1:44:05

        And how does that-

    18. TSThomas Seyfried1:44:06

        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.

    19. PAPeter Attia1:44:12

        But going back to the bruise example, right, so you get a contusion in your thigh, the, the macrophage does play a role in clearing that cellular debris.

    20. TSThomas Seyfried1:44:21

        Yes, yes.

    21. PAPeter Attia1:44:21

        So why doesn't it just effectively do the same thing with the cancer cell-

    22. TSThomas Seyfried1:44:24

        Be-

    23. PAPeter Attia1:44:24

        Or with the soon to be cancer cell?

    24. TSThomas Seyfried1:44:26

        Yeah, because the cell is not recognized as being... It's looks, it looks like it's a part of the local normal epithelial cells, okay? It's just, it's not, it's a, it's not looking at it 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 re- we replace our cells by proliferation.

    25. PAPeter Attia1:44:44

        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"?

    26. TSThomas Seyfried1:44:51

        That that cell... Yes. This cell is hardwired to do what it's supposed to do. It's not like thinking, "Oh, let me, let me problem solve." [laughs] It's not a problem-solving cell. It's hardwired to respond to a particular environmental issue.

    27. PAPeter Attia1:45:03

        I see. So you're, so you're saying the lactate is the fi- is the fire alarm that got it there.

    28. TSThomas Seyfried1:45:07

        Yes.

    29. PAPeter Attia1:45:08

        But then when it gets there, it doesn't see the fire.

    30. TSThomas Seyfried1:45:09

        No. Uh, uh, it, well, it tries to put out the fire, but the problem is w- 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. It's-
13. 1:49:17 – 2:00:30

    Biopsy Disagreement and Extracranial GBM Metastasis

    1. TSThomas Seyfried1:49:17

       Yeah, I think that's, that's correct. And, and what we find now with a number of papers is that needle biopsies that y- are used to dia- diagnose th- the tumors, uh, can create a wounded, even a more aggressive wounded situation in the microenvironment of the tumor, leading to the phenomenon of, of, 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, not here.

    2. PAPeter Attia1:49:51

       But, but wait. W- uh, let's say we do that. We're gonna immediately resect that tumor anyway, so how is that-

    3. TSThomas Seyfried1:49:57

       Well-

    4. PAPeter Attia1:49:57

       How quickly does this process take place?

    5. TSThomas Seyfried1:49:59

       It can take-

    6. PAPeter Attia1:49:59

       Because the wound is between the outside world and the tumor, not between the tumor and the inside world necessarily, especially if that tumor's going to come out, you know, within a few weeks, right?

    7. TSThomas Seyfried1:50:10

       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, 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-

    8. PAPeter Attia1:50:34

       Well, but, but yeah, no, I think what's, what's-

    9. TSThomas Seyfried1:50:36

       So then you can get the cells out r- in a relatively-

    10. PAPeter Attia1:50:37

        Yeah, but I think what's known is that you can seed tumors along the tract-

    11. TSThomas Seyfried1:50:41

        Yes

    12. PAPeter Attia1:50:41

        ... of where you do that. Yes-

    13. TSThomas Seyfried1:50:42

        Yeah

    14. PAPeter Attia1:50:42

        ... 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?

    15. TSThomas Seyfried1:50:53

        Well, it wouldn't be brain metastases right away. It would have to-- That brain metastasis, the secondary metastatic behavior, had ta- has taken a while. There's oth- it's not just the brain.

    16. PAPeter Attia1:51:02

        But h- how does a needle biopsy increase the risk of that?

    17. TSThomas Seyfried1:51:05

        Ne- needle biopsy creates a, um, a more inflamed condition. That's why you call it inflammatory oncotaxis. And you know, 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 s- Johnson & Johnson for uterine, r- removing uterine polyps. Well, you're taking a polyp, and you're grinding it up and creating inflammatory oncotaxis. Now, there might have been th- one polyp out of a thousand that was, that would have this-

    18. PAPeter Attia1:51:35

        Right, but that's very different from the, the... I'm, I'm asking a very specific question, 'cause 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, I'm, I'm still-- I think that's a very different case than the example of-

    19. TSThomas Seyfried1:51:48

        Well, the evidence is clear in some cases, not all cases. Not everybody who goes under a needle biopsy is gonna have metastatic cancer.

    20. PAPeter Attia1:51:56

        No, but that's not the question. I mean, what I'm asking is, is a woman, if you take a thousand women, y- you take, uh, 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?

    21. TSThomas Seyfried1:52:29

        I think so, but I can't be sure because that experiment hasn't been done.

    22. PAPeter Attia1:52:32

        Okay.

    23. TSThomas Seyfried1:52:32

        I'm basing it on what has already been known about needle biopsies facilitating the spread of the tumor.

    24. PAPeter Attia1:52:38

        But I, I, again, I, I'm just being critical of this because I, I, I feel very strongly about not causing panic in people. But I-

    25. TSThomas Seyfried1:52:44

        No, I don't, no

    26. PAPeter Attia1:52:44

        ... I think those data are about needle tract seeding.

    27. TSThomas Seyfried1:52:47

        Yeah. Well, needle tract-

    28. PAPeter Attia1:52:48

        Like, you know, for example, like as you said-

    29. TSThomas Seyfried1:52:49

        Absolutely

    30. PAPeter Attia1:52:50

        ... you have a, you have a liver biopsy-
14. 2:00:30 – 2:11:26

    Cancer Mortality and the Dream Clinical Trial

    1. PAPeter Attia2:00:30

       But just to go back to that, 'cause I'm sorry, it's just, I, I just, I really [laughs] want to make sure people aren't gonna 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.

    2. TSThomas Seyfried2:00:49

       Yeah. Well, I think that we've, we've probably... Now, I'm, I don't want to say, I just want to say that every year we have more and more dead people. This is, this is... And the increase is faster than the general population, okay? So we had 3.8% increase in, in death-

    3. PAPeter Attia2:01:03

       I don't... Is that, is that actually true? Is the age-adjusted, population-adjusted mortality of cancer today higher than it was 50 years ago? I, I think it's about 3 or 4% lower, isn't it?

    4. TSThomas Seyfried2:01:14

       Yeah. Well, I just did the last five years, okay, from 2013 to 2017.

    5. PAPeter Attia2:01:18

       But to test this hypothesis, we'd want to take an even longer time period and go, you know, more extreme-

    6. TSThomas Seyfried2:01:23

       Yeah, yeah

    7. PAPeter Attia2:01:23

       ... as far as like-

    8. TSThomas Seyfried2:01:24

       Yeah

    9. PAPeter Attia2:01:24

       ... you know.

    10. TSThomas Seyfried2:01:25

        I, I mean, every year it's get- uh, there's no year that we have fewer. Th- they're always coming. The dead people are piling up. So, you know, 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 n- 2.9%. Okay. Over the same period, how many Cancer deaths-

    11. PAPeter Attia2:01:47

        Right. But again, a- again, not to, I don't know my epidemiology well enough to make this case, but I'm gonna 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?

    12. TSThomas Seyfried2:02:02

        Uh, well, we have younger people, too, right?

    13. PAPeter Attia2:02:03

        Right, but the majority of cancers are older folks.

    14. TSThomas Seyfried2:02:04

        We have a majority of cancer are older folks, for sure.

    15. PAPeter Attia2:02:06

        So I'm not sure that that, uh, population argument would-

    16. TSThomas Seyfried2:02:09

        Yeah. Well, I don't know

    17. PAPeter Attia2:02:09

        ... it would answer that question, would it?

    18. TSThomas Seyfried2:02:11

        May- well, maybe. There's always a guy you can find. I think all you have to look at is, is the, the numbers of people that are dying from the disease. I mean, that's a fact. You know? That, that-

    19. PAPeter Attia2:02:20

        No, it's a fact, and it's a tragic fact. I, I guess, you know, a 50% reduction in this, 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.

    20. TSThomas Seyfried2:02:37

        Yeah.

    21. PAPeter Attia2:02:38

        Which, which I think you're arguing is unacceptable and understandable.

    22. TSThomas Seyfried2:02:41

        Well, you know, yeah, I'm looking at it from, from the tragedy, and China's 8,100 people a day dying from cancer. I mean, that's the number over there. They may have obviously the big, bigger population, but the problem, it, it's, 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, I think, I wouldn't, I would not be shocked if we had a 50% reduction in, in 10 years. So you, you would-

    23. PAPeter Attia2:03:13

        So, so normally I, I ask people what their dream experiment would be, but I'm, I wanna ask you two. I wanna ask you this question twice. The first one, the first time I'll ask you this question will be the easier one, 'cause 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, what would you wanna put head-to-head to, to definitively ask that question?

    24. TSThomas Seyfried2:03:40

        Okay. So what we do right now is if we do metabolic therapy at all, okay, if we do it at all, it's either standard of care versus standard of care plus metabolic therapy. We're missing the cru- the critical control group, metabolic therapy without standard of care. What are we doing to these patients?

    25. PAPeter Attia2:03:59

        So, so tell me what the experiment would be. Let's d- let's use, uh-

    26. TSThomas Seyfried2:04:01

        Okay

    27. PAPeter Attia2:04:01

        ... breast cancer as an example.

    28. TSThomas Seyfried2:04:02

        Okay, breast cancer. So you have your standard whatever you're doing today.

    29. PAPeter Attia2:04:04

        Yeah.

    30. TSThomas Seyfried2:04:05

        You got a lot of people dying of breast cancer, metastatic breast cancer. So we're gonna now take metabolic therapy, and we're gonna combine it with standard of care, which is what the group in, in, in Turkey had found.
15. 2:11:26 – 2:18:12

    Metabolic Therapy in Practice: Protocol, Surgery and Radiation

    1. PAPeter Attia2:11:26

       And, and where does the surgery take place here? Is the surgery taking place before all of this happens?

    2. TSThomas Seyfried2:11:31

       No. The surgery would take place at some midpoint, okay? The midpoint would be where the surgeon now looks at the tumor and says, "I can take care of this." It's not gonna be a diffuse mass. It's not gonna 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, it, it's much less angry. It's a micro-- It's more demarcated. You can see it on this, in the histological slides. You can see, what the hell happened to this tumor? How come it's, how come it's smaller? How come it's more-- the margins are more sharply demo- 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, we can reduce the death rate by fifty percent if you view the tumor as a metabolic problem rather than a genetic problem. The gene mutations are all downstream epiphenomena. They're red herrings. Even Vogelstein, who still claims that this is a, a-- Bert Vogelstein from John-

    3. PAPeter Attia2:12:35

       Yeah

    4. TSThomas Seyfried2:12:36

       ... he still claims it's a genetic disease, but we're never g- never gonna cure the disease by targeting the genes. There's too many mutations to 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. Why, why... They're being used to train to give dosa- 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, from the treatments. This is absurd. Why are you treat- using radiation and chemo in the first place? Well, we have to stop proliferation. Okay. Well, we-- if they can't generate energy, they're gonna stop proliferating. They're gonna die.

    5. PAPeter Attia2:13:15

       What is the experiment, the clinical trial that you're involved in, in Turkey that you've alluded to?

    6. TSThomas Seyfried2:13:19

       Yeah. So what we, what we do, my colleagues in Turkey do, is they use chemo, but they use the lowest possible dose.

    7. PAPeter Attia2:13:25

       Is it for breast cancer?

    8. TSThomas Seyfried2:13:26

       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, 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. So we know we can press things constantly without harming the body, but we have to pulse, uh, the glutamine issue because we don't want to deprive our normal immune system and gut systems of the very fuel needed to, 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.

    9. PAPeter Attia2:14:05

       Are there any that are in clinical trials in the United States?

    10. TSThomas Seyfried2:14:08

        Yeah. There's a couple. There's, there's a name, there's a few names of them, you know, there. They target various aspects of the glutaminolysis pathway. The problem is we have a drug that's called a, it's a dirty drug. It's, it, 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.

    11. PAPeter Attia2:14:26

        Which drug is that?

    12. TSThomas Seyfried2:14:26

        This is DON, the, the six nor- like 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, you're not-- you're gonna-- the horse is gonna get out, and it's, it's still not gonna 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, to make this all work. Now, there's bits and pieces of it.

    13. PAPeter Attia2:14:49

        And then, and then what are the drugs that are in current clinical trials that are targeting glutamine?

    14. TSThomas Seyfried2:14:53

        Well, there's a BEPTS, I believe, an acronym for another very complicated structure. And then there's a... 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, you can 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, a way in which a previously very effective drug could be less toxic? And both of them, the com- the end result is the same. You're gonna get something that's gonna work far better than, 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, no one's doing this. W-

    15. PAPeter Attia2:15:42

        But now this, this trial in Turkey is doing this?

    16. TSThomas Seyfried2:15:45

        Well, they're not targeting the glutamine. So they're doing, they're doing these other processes, but they-

    17. PAPeter Attia2:15:49

        So it's, it's the glucose, the ketones, the hyperbaric oxygen-

    18. TSThomas Seyfried2:15:53

        Yeah

    19. PAPeter Attia2:15:53

        ... but not pulsing with glutamine.

    20. TSThomas Seyfried2:15:55

        No, no, no.

    21. PAPeter Attia2:15:55

        Not the anti-glutamine.

    22. TSThomas Seyfried2:15:56

        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, uh, which is a green tea extract. But they're not, 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 thirty months, which is far longer than most people with a glio- 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, of therapeutic ketosis, debulk the tumor, most of it, 'cause you never get all GBM. And then we didn't, we didn't do... We were forced into the radiation therapy after three months, even though the guy was doing remarkably well. So this is a... So we said, "Why are we irradiating?" "Well, we have to because it's part of the stand-" Even in Egypt. 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, a headache. His head starts to swell, and they did a, the compression, debulking, 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 gonna make any major advance in brain cancer until we stop irradiating people with the brain because you're creating a bigger problem, um, and this is leading to the demise of all these poor patients. The survival after radiation is almost zero. So, um, and that's, in my mind, it's becoming be- it's due 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 gonna 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 im-improve overall survival. So when I say we can drop death rates by fifty percent in ten years, we're not only dropping death rates, we're massively increasing overall survival and quality of life at the same time. So I have a lot of anecdotal information f- uh, w- 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 this, some of my clinician friends have been telling me this. These guys that are on 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, they're, they're, they're, they're incapacitated.

16. 2:18:12 – 2:25:56

    Cure Potential, GBM Cases and Clinical Trial Obstacles

    1. PAPeter Attia2:18:12

       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 fifty percent, it, there's no lead time bias/therapeutic extension that's gonna do that. That is, that is a paradigm shift in cure, not treatment.

    2. TSThomas Seyfried2:18:32

       I think it's both. I think you're gonna be able to extend dramatically overall survival. You're gonna s- improve dramatically quality of life. And how do we know if we're cured? The, the issue is, is that if you die from a heart disease at eighty-five and you had cancer when you were, when you were fifty, a, a terminal, so-called a terminal disease-

    3. PAPeter Attia2:18:51

       No, I mean, I think we could pick something simpler than that, right? If you are ten years disease-free To a first order approximation, you're cancer-free, right? If you had colon cancer 10 years ago and, you know, 10 years later you die of a heart attack, I, I think it's safe to say you died of heart disease, even if on a autopsy they find dormant cancer cells.

    4. TSThomas Seyfried2:19:12

       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 gotta, you also have to put into, into perspective what effect does the treatments have on your overall long-term survival as well, right? So Dana-Farber down here just opened up a branch of, of medicine called cancer survivor medicine. It appears that many people treated with standards of care are suffering from 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, you're, it's unlikely you're gonna-

    5. PAPeter Attia2:19:50

       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, uh, if he hadn't undergone radiation for the GBM, y- your belief is he could have actually had a cure?

    6. TSThomas Seyfried2:20:07

       I don't know because we, we can't know. Like you said, we'd have to wait 10 years-

    7. PAPeter Attia2:20:12

       Yeah

    8. TSThomas Seyfried2:20:12

       ... to know that. So if we were to institute an aggressive metabolic program for managing cancer-

    9. PAPeter Attia2:20:17

       But it seems GBM would be the place to do it, right? Because it's, you know, it unfortunately-

    10. TSThomas Seyfried2:20:22

        It would be

    11. PAPeter Attia2:20:22

        ... is such a uniformly fatal cancer.

    12. TSThomas Seyfried2:20:24

        And it's fatal because of the treatment that they're giving these. This combination of the, of, of what they're doing to the patient, uh, a- as well as the tumor.

    13. PAPeter Attia2:20:32

        The, the problem clinically, right, is that the mass effect doesn't give you a lot of flexibility to delay surgery. So between corticosteroids-

    14. TSThomas Seyfried2:20:42

        Yeah. Yeah

    15. PAPeter Attia2:20:42

        ... and radiation, when a patient pr- some of most patients present with GDM, not, not GBM, not as incidental findings, they have symptoms from the mass effect.

    16. TSThomas Seyfried2:20:50

        Yeah.

    17. PAPeter Attia2:20:51

        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-

    18. TSThomas Seyfried2:20:59

        Yes

    19. PAPeter Attia2:20:59

        ... hemiparesis and the, he's got a GBM."

    20. TSThomas Seyfried2:21:03

        Right.

    21. PAPeter Attia2:21:03

        The idea that we're gonna wait a month to put him on a ketogenic diet when I need to either cut that thing out now or radiate him or, or put him on corticosteroids, I... So, so in other words, there's a, this is gonna be a very difficult thing to study.

    22. TSThomas Seyfried2:21:15

        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, but they're a lot of my friends. I said, "What's the stat? What do we do here?" He said, "Occasionally, if you have brain herniation po- possibility, the patient will 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.

    23. PAPeter Attia2:21:40

        Yeah. Of, of the three-

    24. TSThomas Seyfried2:21:41

        Yeah

    25. PAPeter Attia2:21:41

        ... what would be the most evil in your mind, uh, meaning metabolically evil, the radiation, the corticosteroid, or the surgery?

    26. TSThomas Seyfried2:21:47

        Oh, clearly the steroids and the radiation. Surgery s- su-

    27. PAPeter Attia2:21:50

        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.

    28. TSThomas Seyfried2:22:00

        Yeah. I think, I think this is a, a, uh, the strategy that watchful, 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 lo- you live longer on debulking the more you can debulk the tumor. So if we can shrink the tumor down like we did to the, the, on our Egyptian pa- we waited three weeks. We put him under incredible therapeutic fasting, water only, 900 k- ketogenic diet. They did a very awake, good-

    29. PAPeter Attia2:22:27

        900.

    30. TSThomas Seyfried2:22:27

        900 calories, uh, kilocalories.

Episode duration: 2:48:20