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

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful top performing individuals in the world. And this podcast

00:00:23.620 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.020 and other topics at peteratiyahmd.com.

00:00:41.420 Hello, everyone. Welcome to this week's episode of the Peter Atiyah Drive. My guest this week is

00:00:47.540 Professor Tom Seyfried, who many of you will know, but I suspect an equal number of you will not know.

00:00:53.020 Tom has come to us through many channels, meaning the requests to speak with Tom have come on many

00:01:00.720 levels. There's been a lot of requests through social media, through the site. And of course,

00:01:06.680 based on our discussions with Dom D'Agostino, Tom has been front of mind for quite a while.

00:01:12.120 This is my first time meeting Tom, but I feel sort of like I know him because I've read so much of his

00:01:18.460 work. And Bob Kaplan, who, of course, you all know as my trusty right-hand guy who lives in Boston,

00:01:25.560 actually takes a course from Tom. And he's taken a course in the past and continues to

00:01:30.960 just wander around Tom's office and just hang out with him overall. So in some ways,

00:01:35.980 this felt kind of familiar, though it was my first time meeting Tom. Tom's background is that he's got

00:01:40.160 a PhD in genetics and biochemistry from the University of Illinois. Got that in the mid-70s and a bunch of

00:01:44.960 other distinctions that I'm not going to go into because we're going to link to all that stuff. He did

00:01:48.880 his postdoc in the Department of Neurology at Yale, and it was there that he first became interested

00:01:54.400 in ketones because of their application in the amelioration of recalcitrant seizures. As we get into

00:02:02.920 in the episode, that led to his interest in cancer, which is now his focus. Tom has published over 150

00:02:10.560 peer-reviewed publications. He's the author of numerous books, textbooks, etc., including kind

00:02:17.180 of a treatise on this. So his magnum opus is effectively a book called Cancer as a Metabolic

00:02:24.060 Disease. I probably got my first copy of this a few years ago, and in many ways, that's what sort of

00:02:29.520 felt quite familiar in speaking with him. He's currently a professor at Boston College, and his research

00:02:35.380 today focuses on the mechanisms by which metabolic therapies can manage chronic diseases such as

00:02:40.160 epilepsy, neurodegenerative lipid storage diseases, and above all, cancer. In this episode, we talk

00:02:46.860 about Tom's background, as I sort of alluded to, his work in epilepsy and how that led him to the

00:02:51.500 interest in caloric restriction and ketosis. We revisit the man, the legend, Odo Warburg, and talk

00:02:56.960 about the Warburg effect and Warburg's point of view on these things. And I do push him a little bit on

00:03:03.400 this because I want to point out that it's not entirely clear amongst people what the Warburg effect

00:03:08.460 really implies and how ubiquitous it is. And I have to be honest with you, I don't necessarily share

00:03:13.860 Tom's views on a number of these things. So I wanted to do my best to sort of represent as many

00:03:19.700 other views as possible. But at the same time, I hope the discussion is helpful. We get into a bunch

00:03:23.980 of the semantics. I knew this was a very technical topic, and I know that not everybody has the luxury

00:03:28.500 of listening to this while they're reviewing the show notes. So we do go over the differences

00:03:33.760 between respiration or oxidative phosphorylation and fermentation. It's very important to understand

00:03:38.260 this. So one thing to keep in mind with this podcast, and frankly, any of the more technical

00:03:41.880 episodes we do, if you're struggling with a concept, hit pause. I don't think it's worth sort

00:03:48.080 of going through these not understanding them. I think it's cool to listen to this, hit pause,

00:03:52.580 go back, hit Wikipedia, ping us with a question on social media or whatever if there's a concept

00:03:57.560 that's stumping you. But this is obviously going to be one of the more important concepts.

00:04:00.740 If you can't understand the difference between respiration, oxidative phosphorylation,

00:04:04.660 as it were, and fermentation, then a lot of this won't make sense. We also get into this

00:04:08.700 idea of substrate level phosphorylation, a very important concept, and the fermentation

00:04:13.020 of glucose. We also talk a lot about glutamine. This is something that I haven't spent a lot

00:04:17.600 of time talking about in the past. I think I do touch on it a little bit with Dom D'Agostino,

00:04:21.700 but we get into it in much greater fashion. And we, of course, get into ultimately the fundamental

00:04:28.840 question that I think people who are interested in metabolic therapies for questions have to be

00:04:33.540 able to answer, which is, is cancer primarily a metabolic disease, meaning a disease whose origin

00:04:39.680 arrives in the mitochondria or in the metabolic machinery of the cell? Or is it primarily a genetic

00:04:45.660 disease where sometimes you will and sometimes you won't sustain mitochondrial damage? Now, I have to,

00:04:53.860 you know, and you'll see this in the interview. It's not entirely clear to me that I buy the argument

00:04:57.840 that cancer is entirely a metabolic disease, though, as some of you will know, I am very

00:05:02.680 bullish on the use of metabolic therapies in cancer, but I'm also very bullish on the use of

00:05:08.100 immunotherapy in cancer and, when appropriate, chemotherapy in cancer. So, you know, my view is

00:05:13.620 that cancer is about as hard a disease as there is ever going to be to target, and therefore, we ought

00:05:18.860 to turn our attention to as many legs of the stool as possible and not just one. I think the discussion

00:05:24.600 gets a little bit heated at one point when I take issue with something Tom said about suggesting that

00:05:31.040 biopsies could exacerbate cancer. I really don't want anybody to come out of this believing that

00:05:37.540 having a biopsy is going to increase their risk of metastatic cancer. I think that anyone's entitled to

00:05:43.760 a hypothesis, but to my knowledge, there are absolutely no evidence to support that claim.

00:05:48.480 We talk a lot about a particular type of cancer called glioblastoma multiforme, GBM, also known as

00:05:56.340 a grade four astrocytoma. This is, of course, a cancer that if you haven't heard of it, you've

00:06:01.300 certainly heard of its effect. John McCain, who recently passed away, suffered from this. I lost a

00:06:07.600 friend to this when I was younger, and I think that if you know somebody who has died of brain cancer,

00:06:12.800 the chances are there's a pretty good chance this is the cancer they had. This is one of those

00:06:17.040 cancers that gives cancer a bad name, and in all fairness, I don't think there's ever been a true

00:06:22.480 documented survivor of this cancer. It also may provide one of the more interesting model systems

00:06:28.220 to study metabolic therapies for cancer. I guess the most important thing we close with is I sort

00:06:33.860 of pushed Tom a little bit on what experiment he would want to see or do to advance the thinking in

00:06:39.680 this field. In many ways, Tom's a little bit of a guy that's on the sidelines of, you know,

00:06:44.600 sort of mainstream cancer. These views, these metabolic fuels, unfortunately, unfortunately,

00:06:49.320 in my view, don't get the attention they deserve. And other people that I'm going to be talking with

00:06:54.700 in the future, such as Sid Mukherjee and Lou Cantley, are going to be some, I think some of the people

00:07:00.080 who are now starting to see through their own research, some of the potential applications for

00:07:05.860 these things. And so I think that in many ways, the problems that Tom has been working on for the

00:07:10.980 last 30 or 40 years are very slowly beginning to gain acceptance. And I don't like to use the word

00:07:17.560 mainstream, but in, I think you know what I mean, in the more mainstream circles of oncology.

00:07:22.040 This interview does get technical at times. And so as is the case with virtually all of our

00:07:26.460 interviews, please pay attention to the show notes if you're having difficulty, if for no other reason

00:07:31.000 than the fact that a heck of a lot of work goes into preparing them on the part of our analytical team.

00:07:35.880 If you like this podcast, I would ask of you very kindly to go and leave a review at iTunes.

00:07:44.620 And I suppose if you don't like this podcast, you can also do that. Lastly, if you are interested

00:07:49.900 in receiving a weekly email, which comes out every Sunday morning from me, that usually talks about

00:07:54.900 something I've done that week, something I've learned that week, something that is hopefully of

00:07:59.300 interest to you. By all means, sign up for that at peteratiamd.com. And I think that's pretty much

00:08:06.360 all I want to say as we go into this. So with that said, please give it up for my guest today,

00:08:11.320 Dr. Tom Seyfried.

00:08:15.660 Hey, Tom, how are you?

00:08:16.860 Well, thank you very much.

00:08:17.940 Well, thank you so much for making time. I know you've got a long lineup of students outside your

00:08:22.600 office here who are kind of pissed at me for sitting here taking up time when you could be answering

00:08:26.640 their questions. So they'll recover. You know, a lot of people have been sort of reaching out to

00:08:33.700 me on social media and saying, you know, you've got to have Tom on, you've got to have Tom on,

00:08:36.720 you know, the podcast with Dom was excellent, but there's so much more we want to understand

00:08:39.780 about cancer. And, you know, certainly cancer is something near and dear to my heart. I did my

00:08:44.480 fellowship in oncology. And, but at the same time, I think I understand cancer far less than I

00:08:49.360 understand things that I didn't formally train in. Like, I think I have a better understanding,

00:08:52.780 for example, of heart disease than I do of cancer. So I'm really excited to explore a lot

00:08:57.560 of topics today and acknowledge that we probably won't even scratch the surface of all that you

00:09:02.720 think about. But all that said, how did you get interested in this?

00:09:06.260 We started it when I was at Yale University Department of Neurology, where we had been

00:09:10.540 working on epilepsy and lipid storage diseases and gangliosides, basically, as a complex lipid

00:09:16.360 molecules. And one of the individuals that I was working with at that time, Robert Yu,

00:09:21.700 was my mentor at the time, he had done some research on ganglioside changes in tumors.

00:09:27.220 And, you know, we had been looking at that. And I said, you know, there was some interesting

00:09:31.860 molecules in those tumor cells. So I also knew Dennis Spencer, who was the chief of neurosurgery

00:09:39.100 at the time at Yale. And he said, why don't you come up to the operating room with me and I'll get

00:09:45.240 you a nice piece of glioblastoma from a patient. And, you know, I'm a basic scientist. I'm not a

00:09:50.360 clinician. I don't know what's going on. So I said, sure. He'd come into the operating room.

00:09:55.380 And it was kind of an experience that I'll never forget, having someone take a tumor out of

00:10:00.740 someone's head. And they were asking me all kinds of questions like, you know, do you think we should

00:10:04.840 put pellets of radiation in the cavity and, you know, all this kind of stuff? And of course,

00:10:09.220 I didn't know. I said, I'm here to look at the ganglioside pattern in the tumor. I don't know how to treat

00:10:13.940 the cancer or anything like this. But in any event, we had then started making our own brain

00:10:19.460 tumors in the mouse based on the work of Harry Zimmerman, who started the first school of

00:10:24.700 neuropathology in the United States at Yale University in the back of the 1930s. And he was

00:10:29.340 still alive at the time. He lived to be 98 years old or something. So I was interested in doing

00:10:35.360 comparative studies of glycolipids in human and mouse brain tumors to see whether or not we can come to

00:10:42.860 some common changes. And that's how we got started, pretty much looking at comparative

00:10:48.560 biochemical profiles between human tumors and mouse tumors. And there was some similarities,

00:10:53.720 but there were many differences as well. But we didn't get into the kind of therapeutic

00:10:58.260 evaluation of these tumors until we also had a huge program in epilepsy, mapping genes for epilepsy.

00:11:05.200 We did a lot of things at Yale. Everybody's working on the glycolipids of the tumors,

00:11:09.220 glycolipids of developing brain, lipid storage diseases, and epilepsy. And I wrote a grant

00:11:16.820 internally at Yale, which was rejected, asking about ketogenic diets.

00:11:22.940 And what year was this?

00:11:23.780 This was back in the late 70s, early 80s, maybe, 1980. And they said, oh, nobody's interested in

00:11:31.100 ketogenic diets. It's kind of passe.

00:11:32.860 This was before the work at Hopkins or?

00:11:35.960 Yeah. Hopkins, John Freeman was a friend of mine too, who was the godfather of ketogenic diets.

00:11:41.980 He was the one that saved Jim Abrams' son, Charlie. And Jim was a movie director. And his friend,

00:11:49.460 Meryl Streep, made the movie, First Do No Harm, which was based in part on Jim's experience with

00:11:56.840 his son. But I wasn't connected at that time to Abrams or any of that stuff. That was even before

00:12:02.180 the Charlie Foundation. I just had this inkling that maybe ketogenic diet would be interesting

00:12:07.460 to test against some of the epilepsy models that I was working with.

00:12:10.580 But does that mean you suspected that something to do with glucose metabolism was-

00:12:14.720 No, nothing. I just thought it was an interesting approach to a non-drug approach for seizures.

00:12:21.200 And anyway, the grant was summarily rejected. So I said, well, nobody's interested in this.

00:12:25.300 So I left Yale and I came up to Boston College here, start a program. And then we were here from,

00:12:30.700 then it was 10 years, 15 years later when we developed some of the best animal models for

00:12:35.780 epilepsy. And we were looking at brain biochemistry and epileptic seizures and the genes that caused

00:12:41.720 epilepsy. And then one of my PhD students, Marianna Tran, says, oh, they're having a big meeting out

00:12:46.900 in Washington on ketogenic diets for epilepsy. And maybe our model would be appropriate for this.

00:12:52.840 I said, nah, this is, you know, I says, after my experience at Yale, I said, nobody's interested 0.97

00:12:58.040 in this crap anyway. 0.98

00:12:59.440 You're still traumatized by the grant. 1.00

00:13:01.440 Yeah, yeah, yeah. So I said, they're not in, you know, I got a summarily rejected that says,

00:13:05.280 this is nobody interested in ketogenic diets. So anyway, she said, hold on a minute. So I said,

00:13:10.020 I had a few extra bucks in the grant. So I said, okay, go on out there. In fact, she wrote a little

00:13:14.620 blurb and they funded her to go out there. So she comes back and starts telling me about, wow,

00:13:20.620 you can't believe what I saw out there. All these guys are interested in this ketogenic diet. And

00:13:24.700 this guy, Jim Abrams, and he wants to start this foundation called the Charlie Foundation. And it

00:13:31.140 was like to study epilepsy and ketogenic diets and stuff. So I said, all right, what the hell? So we 0.65

00:13:37.260 started to put them on the mice. And it was funny because we didn't know what we were doing. But then

00:13:42.420 at the same time, it was, two things came together at the same time. We were studying gangliocytes for

00:13:47.900 lipid storage diseases. And there was a drug company over in England that gave us this new

00:13:51.640 drug that was supposed to stop ganglioside synthesis and therefore reduce the storage in

00:13:55.980 the brain. Of course, at that time at Boston College, they didn't charge me for animals,

00:14:03.300 which they do now, which is a tragedy because you can really do a lot of work. The damn mice cost so 0.99

00:14:07.860 much money. And there were so fewer restrictions. I mean, we'd followed all of the animal care 1.00

00:14:12.380 protocols, but we had access to a large number. So we could do experiments that you

00:14:17.140 couldn't do anywhere else. So when we got the drug from the company, we were feeding the drug to the

00:14:23.080 mice. And we looked at the ganglioside. Yeah, it's really down. But so was the body weight. And then

00:14:27.860 when we put the control group in, we found out that, yeah, the tumors shrunk and the gangliosides

00:14:32.740 were reduced from this drug. But then the body weight was also reduced.

00:14:37.220 And the controls were also, they're both animals being fed ad lib?

00:14:40.380 Ad libidum. One had the drug, one didn't.

00:14:42.720 Okay. So the drug somehow either reduced intake or increased expenditure.

00:14:46.240 We don't know, but it's the body weights were reduced by about 15 or 20%. So, and the tumors

00:14:51.560 were significantly reduced by about 50, 60%. So I told the company that, you know, I just threw

00:14:56.880 them on. I just, this was a pilot study. I told the company that your drug seems to really shrink

00:15:01.560 brain tumors. And they go, wow, Jesus, this is a much bigger market than say Tay-Sachs disease,

00:15:06.560 right? So that's when they gave me $200,000 to investigate the mechanism by which their drug was

00:15:13.520 stopping brain cancer. Because I showed them the data and they were, they were all excited.

00:15:17.920 So we then began to investigate this and Perna Mukherjee, Dr. Mukherjee who worked, started with

00:15:22.900 me. I said, hey, Perna, I hired her specifically to start looking at this. And then when we realized

00:15:28.820 that, you know, what's, what's working? She said, you know, a lot of times these drugs work through

00:15:34.040 calorie restriction. So I said, well, why don't we put a control group? We all decided, let's put a

00:15:39.620 control group for body weights. And then we just, one, one was the, the guys with the drug and losing

00:15:45.220 weight. The other guys would just take the food away from them. So the body weights would be

00:15:48.360 absolutely identical. So they were pair fed. It wasn't pair fed. One, uh, one group was eating

00:15:53.600 ad libitum and they were losing body weight. And the other group, uh, we had to restrict the

00:15:59.160 calories to match, to match the body weight. So they were, they're pair weighted. Yes. And it weighted.

00:16:04.280 And then we evaluated this and the tumors were exactly the same size. So it had nothing to do

00:16:09.780 with the drug. Even though the drug was working on the targeted molecule, it wasn't the targeted

00:16:14.760 molecule that was, was responsible for this. So that's when we also decided with the epilepsy

00:16:21.660 overlapping, does the cat, does the ketogenic diet work through calorie restriction? Because many of

00:16:26.400 these children that get ketogenic diets, they have a very restricted calories and you have to,

00:16:30.560 you have to give, um, very small, you can't let kids eat massive amounts of fat because invariably

00:16:37.220 John Freeman told me it doesn't, the diet doesn't work if they just like one out of two or 300 kids

00:16:41.960 just loves to eat all this fat and the, and the seizures don't go away. So we, in other words,

00:16:46.980 the, the thinking at the time was there is some amount of caloric restriction that is necessary

00:16:51.620 within the context of the ketosis to also affect the epileptic seizures. Yes, absolutely. But you have to

00:16:57.780 be very careful because many of these children are on the growth spurt. So you have to be careful

00:17:01.680 on how much restriction you give. And the other thing, of course, it's self-restricted. There's

00:17:06.100 several physiological systems in our body that when you eat a lot of fat, you just don't eat a lot of

00:17:10.600 calories. It's a turnoff. It works through the vagus nerve. The hormone cholecystokinin is kind

00:17:16.680 of an appetite suppressor. It affects the vagus nerve, which then stops the appetite. You don't eat as much.

00:17:22.100 So I have so many stories. So I was sitting on a bus one day.

00:17:26.480 You're on the right podcast, Tom, because we don't have time restrictions.

00:17:30.080 Yeah, but listen, so they made this thing called the vagal nerve stimulator. And it was made by a 0.97

00:17:36.320 company. I can't remember the name of it. Made a fortune. They would implant the stimulator into

00:17:40.680 the persons who has epilepsy and it would send out things to stimulate the vagus nerve. And I was

00:17:46.420 sitting on the bus with this guy from Norway. And he says, I said, you're putting this in the

00:17:49.700 patient. Yeah, we're putting this in the patients. How does it work? Yeah, it seems to work really

00:17:52.700 good. I said, how much is it? He says, well, the operation is like $4,000, but the device,

00:17:59.420 it was like $15,000 or $16,000. But they were putting them in all these epileptic patients and

00:18:04.220 they're working. I said, how does it work? He said, I don't know, but it works. So I said,

00:18:07.620 I didn't know. I'm sitting on the bus. I don't know. We're going to MGM Studios down in Florida.

00:18:12.660 They closed the whole place down in the middle of the week in December so that they could attract all the 1.00

00:18:19.520 epileptologists to use their device to put into these patients. It's one of these kinds of things.

00:18:24.140 So anyway, it comes back when we were working on ketogenic diets and calorie restriction,

00:18:28.540 we realized that humans have this internal system to stop calories. And if you don't stop the

00:18:34.700 calories, invariably, you don't get the management of the seizures. So we, in our parallel studies in

00:18:41.960 epilepsy with mice and cancer and all this other stuff, we started to learn what's working in the

00:18:48.680 patients. How do we translate what's working in the patients into the mice? The mice can be another

00:18:53.460 source of information that we can feed back. And we published this big paper on calorie restriction

00:18:59.080 and that the ketogenic diet was working largely through calorie restriction and maintaining low

00:19:05.040 blood sugar levels was the key to maintaining control of seizures.

00:19:08.820 Now, if you had a, I don't know if you did this experiment, but if you took animals on an equally

00:19:13.320 low caloric diet that was not ketogenic, so let's just say a very high carbohydrate, low fat diet,

00:19:19.880 where presumably glucose levels would be higher, even though they would still be calorically

00:19:23.980 restricted, would you get the same anti-seizure benefit?

00:19:26.680 The same results. Exactly. So because what was happening is that when the body is restricted of

00:19:31.640 calories, you then make ketones. So the level of ketosis was also seen in the calories. It would be

00:19:37.560 like a human doing what are only fasting.

00:19:39.440 So how calorically restricted did they need to be if they were not on a ketogenic diet?

00:19:43.980 40%, 30 to 5 to 40% restriction. And then we did some studies, another group, we found out that

00:19:48.900 35 to 40% restriction of calories in the mouse equates to a water-only therapeutic fasting in

00:19:55.540 humans. And that's because the- Yeah, their metabolism is-

00:19:58.640 Right, seven or eight times higher than that of a man. So humans can achieve much higher ketosis than a

00:20:03.900 mouse can. And the mouse, so one week, a one-day water-only fast in a mouse is like a seven-day

00:20:10.000 water-only fast in a human. And the blood sugars go down, the ketones go up.

00:20:13.540 IRBs don't allow you to fast mice that long anymore, do they?

00:20:16.860 Oh yeah. I mean, as long as they're healthy. Calorie restriction is generally a healthy thing.

00:20:23.000 You don't want to over-restrict because then you put into a nutritional imbalance and you don't want

00:20:28.360 to go to the level of what we call starvation. This is another. Calorie restriction is healthy

00:20:33.620 up to the point where you start breaking down muscle. If you start breaking down muscle,

00:20:37.560 then you enter into a new physiological state called starvation. And that's very pathological.

00:20:43.180 You don't ever want to go to that digression. So some people, they get so carried away with

00:20:47.720 water-only fasting, they can enter into starvation mode. And I know this for a fact because I used to

00:20:53.260 spend a lot of time with George Cahill, who used to run the Joslyn Diabetes Centers down here in

00:20:57.960 Boston. And he and I would talk for hours and hours with Bud Veach at the NIH about how long

00:21:03.240 people can go with this transition over from therapeutic fasting into starvation. And also

00:21:09.360 the body builds. It's like anything. Your body gets accustomed. You can go a long time without

00:21:14.400 eating if you're in shape, if you've done this. But it depends on what your body weight is,

00:21:19.840 how old you are. It depends on a lot of different things, how long you can go without eating.

00:21:24.360 But the bottom line is that we were trying to develop a therapy and figure out the mechanisms

00:21:30.540 by which ketogenic diets were therapeutic. Now, going back to the Cahill stuff for a moment

00:21:35.500 before we come back to that, did you have a sense or did George have a sense of when those patients

00:21:41.400 are in a negative nitrogen balance? And I assume it matters as to what their starting weight is and

00:21:46.800 muscle mass and things like that. But were there general rules about once you cross over that point

00:21:52.420 where you're basically pulling nitrogen out of the muscle?

00:21:56.280 Right, right. And he got those data actually from the 10 guys that starved to death in May's prison

00:22:02.180 in Northern Ireland, Bobby Sands and that group actually. He was there monitoring their blood

00:22:07.480 work while they were dying of starvation.

00:22:10.280 These were prisoners that they were fasting as a protest, correct?

00:22:14.280 Yes. They made a movie out of it, Every Mother's Son, about it. There was 10 Irishmen that were-

00:22:20.080 How long did they live on average?

00:22:21.740 They averaged, I think, he had the data. He was never able to publish it. The British government

00:22:26.560 was on top of him about that. But he was able to collect the data and shared some of that stuff.

00:22:32.460 It was very interesting. It's a horrible thing. It's like one of the worst ways to die is starvation.

00:22:37.420 So what happens, your diaphragm is the last muscle that will be digested. And there's a momentum

00:22:43.700 that starts. Now you have to realize that these guys that did this-

00:22:48.700 So they don't die of just acidosis. It's actually the-

00:22:52.380 You drown in your own body fluids, basically. Jeez, it's brutal. Because what happens is once your

00:22:58.660 diaphragm can't work, your lungs fill up with fluids and you drown in your own fluids.

00:23:04.020 And the diaphragm presumably stops working because of either the loss of muscle or the

00:23:08.260 electrolyte imbalance.

00:23:09.440 Yeah, both. A combination of both. And then you can't stop it. Once the momentum starts-

00:23:16.220 It's like these horrible hiccups, right?

00:23:17.540 Yeah. Well, once the momentum starts, it seems like they try to do an intervention

00:23:22.020 on a couple of the guys and they weren't able to reverse it. So it was pretty horrific.

00:23:27.040 Now, those guys were all young Irishmen, you know, in their 20s and 30s. I don't know what

00:23:32.580 the oldest guy was, but they lived from, I don't know, 68 to, I don't know, 85, 90 days without

00:23:38.680 any food, just water. But then he subsequently fasted these very obese people.

00:23:44.100 For 40 days?

00:23:45.140 Longer, for six months, eight months.

00:23:47.000 Oh, wow.

00:23:47.480 Yeah. He has the data. One guy, a postman, lost his job, weighed 450 pounds or something,

00:23:53.680 couldn't deliver the mail. So they put him on the water-only fasting for six months,

00:23:59.260 I think, six or eight months. Guy lost 250 pounds.

00:24:01.860 This is different from the guy who, there was a single case report of a patient who weighed

00:24:07.160 a little over 400 pounds and did a 382-day fast.

00:24:11.000 Yeah.

00:24:11.160 But I didn't realize that was Cahill that was overseeing that.

00:24:13.520 I don't know if that was Cahill. There was another, there's a couple of them.

00:24:16.980 Okay.

00:24:17.360 But he was overseeing, he showed us the data on this one guy, the postman. And, you know,

00:24:23.620 and the issue, of course, is I don't know if he took many supplements because your body fat

00:24:28.080 holds a lot of vitamins, fat-soluble vitamins. The minerals come from your bones. The liver

00:24:33.240 holds an awful lot of B vitamins and things like this. I think there were supplements over the

00:24:38.360 course, but they weren't, you don't need a lot of supplements. Your body holds a lot. We evolved

00:24:43.080 as a species to starve. I mean, our existence today is dependent on our ability to go long

00:24:49.460 periods of time without eating. We don't receive that anymore, but-

00:24:53.480 Yeah, yeah. And it seems that our ability to access minerals and vitamins is highly dependent

00:24:59.960 on our nutritional state. In other words, your need for those things tends to go up in a fed state.

00:25:05.500 Yeah. At least according to some research I've seen.

00:25:09.240 Yeah, you're right. And our ancestors were hardened people. You know, their bodies were

00:25:14.260 already acclimated to a starvation mode. So they were very efficient in maintaining mineral and

00:25:20.560 nutrient balances. I think in our society today, and this is purely speculation, I think a lot of the

00:25:25.980 foods are depleted in the kinds of nutrients that we would need. Therefore, some people are almost

00:25:31.320 like in a starvation mode, but they're eating food that has no nutritional value. And consequently,

00:25:36.980 you store a lot of fat. Because the body doesn't usually get rid of sugar. You know, as I said,

00:25:43.160 sugar is stored. It's not, you know, pee out sugar unless you have type 1 diabetes or something.

00:25:48.200 The body has all these filtration systems to keep carbs, which is then transferred to fat 0.59

00:25:53.080 and stored as fat. That's our energy to keep us alive when there's no food. But all these ideas and

00:25:59.440 things were developing when we were doing the epilepsy studies. And it became clear that calorie

00:26:04.600 restriction was a key mechanism by which the ketogenic diet was working. And we have since

00:26:10.140 then seen in numerous children with epilepsy that breakthrough seizures will occur when blood sugar

00:26:16.660 spikes. Define spike in that very specific case. How high does it need to be in milligrams per

00:26:21.480 deciliter? Yeah, it doesn't really, for managing epilepsy, there's many cases where it just has to go a

00:26:25.840 little bit above the baseline. So kids will have a very low 70, 68, 65 milligrams per deciliter.

00:26:33.240 They'll grab a cupcake at a party or whatever and spikes up to 120 or whatever. And then you'll get

00:26:38.780 a breakthrough seizure. And do you believe that it is the absolute value of 120 in that case? Or do you

00:26:44.740 believe it's the D by DT, like meaning the rate of change of the glucose? We can't know that. It hasn't

00:26:50.820 been done effectively. All we know is from the clinicians and the nurses that have told me all

00:26:55.580 this information. And of course, when your child has a breakthrough seizure, nobody likes to see a

00:27:00.880 kid seizing. I mean, it's traumatic. It's not a pleasant thing. So once they realize that the kids

00:27:07.660 have to maintain this very stable, the parents are very, very restrictive of these kids because they

00:27:15.180 don't want to see their child seize. So they're very restrictive. So when we do the same thing for

00:27:19.700 cancer, the problem with cancer is you don't see a breakthrough seizure. You don't see a group of

00:27:25.660 tumor cells starting to grow faster. You don't see the immediate effects, but they're there, but you

00:27:30.020 just can't see them. With epilepsy, you have a very visible, clear indication that something went wrong.

00:27:35.880 And invariably, there's a spike in glucose. Now, what's very interesting is in these kids,

00:27:40.360 they could be maintained for months without a single seizure. And then one drink of a grape juice

00:27:45.840 or whatever the hell, boom, breakthrough seizure within sometimes minutes from the time you took

00:27:50.800 the... So it's a very, they can flip back, but then they can also get back on track again. They don't

00:27:55.740 have a large number of seizures. They can just, they can get back on track. But it's a very sensitive

00:28:00.520 system in our brains. And as John told me, John Freeman, he says, we don't understand that if a kid

00:28:06.780 has maintained seizure-free or minimal seizures for long periods of time on ketogenic diets,

00:28:13.020 and then we remove the diet, they seem to be managed. In other words, they don't return to their

00:28:18.980 multiple seizures that they would have had every day. So he doesn't know if it was because the diet

00:28:24.320 did something fundamental or they outgrew the seizure or whatever. It was, again, these are areas

00:28:30.060 in epilepsy that are under active investigation by a lot of...

00:28:32.840 But it's interesting. It's almost like a reset, right? I mean, one of the things that impressed

00:28:35.820 me about reading the case studies of these very, very long fasts is that in the reports

00:28:42.360 that are published several years later, many of the subjects maintain their new weight-reduced state,

00:28:49.540 which is a bit counterintuitive based on what we know today about traditional dieting approaches

00:28:55.180 where everybody sort of will return back to baseline. And so it begs the question, right? When you starve

00:29:01.100 this person for six months, do they completely change the way they eat on the other side

00:29:06.400 because of a behavioral shift or is it a physiologic shift, meaning their metabolism has been kind of

00:29:11.660 quote-unquote fixed?

00:29:12.560 Yeah. Well, I think it's probably a combination of both. I mean, again, these are very complicated

00:29:16.660 physiological processes. You know, they call it the thrifty gene. That was a term. It's not one

00:29:22.360 gene. It's like the thrifty physiology. If you do yo-yo dieting, I mean, you can be screwed up for a long

00:29:27.460 period of time. Those things all have loose ends. There's nothing that we have found that's absolutely

00:29:34.940 consistent in all patients all the time when it comes to those kinds of things. And that's why

00:29:40.780 they're always interesting to talk about because someone always has some new people, new idea about

00:29:45.200 something that they've seen. It kind of fits in a little bit with what everybody else is. I don't

00:29:49.960 really dwell, engage in those kinds of things as far as our research is concerned. You know, we know

00:29:55.080 about them. We talk about them, but we don't, other than the calorie restriction that we introduce

00:30:00.140 into the mice. And then when we found out that the calorie restriction and the ketogenic diets were

00:30:05.080 working. So people say, well, why don't you just do calorie restriction? Because, you know, cancer,

00:30:10.140 back to cancer, we don't like to restrict. The term restriction, even the term, you already got a

00:30:16.600 disease, now you have to be restricted. You know, it's like, so ketogenic diets are a little,

00:30:21.240 takes the sting out of a therapeutic fast. And they can also replicate some of the same

00:30:26.100 physiological changes. The key is to lower the blood sugar and elevate the ketones. And that's

00:30:31.400 what ketogenic diets do for managing epilepsy. And they do the same thing for cancer. The issue,

00:30:37.700 of course, is we don't know the mechanism by which lowering glucose and elevating ketones is

00:30:43.340 responsible for the management of the seizure. This is under an active investigation by a lot of labs.

00:30:49.020 The actual mechanism. Is it the elevation of the ketones? Is it the reduction of the glucose?

00:30:53.860 Or is it some combination of the two? But for cancer, it becomes very clear. The mechanism of

00:30:59.680 action is very clear for how this kills cancer cells. It's based on Otto Warburg's theory.

00:31:06.480 So when we started to do this and realized that calorie restriction was shrinking these tumors down

00:31:11.800 massively, you know, based on the drug that I told you about, because it was working through

00:31:16.880 calorie restriction. Then I said, you know, how is calorie restriction stopping tumors?

00:31:21.620 And then we realized that it was lowering blood sugar. So we started measuring blood sugar in

00:31:25.760 these calorie-restricted mice and measuring ketones. And we were seeing that we were getting

00:31:30.520 these major shifts. And then we said, you know, then it became clear who was the guy who did this

00:31:34.720 or thought about. And it was Warburg. Now, he wasn't doing ketogenic diets. Had he done and known

00:31:39.440 about that, I think he would have been able to crack this cancer thing far, far earlier than it.

00:31:44.340 He didn't do ketogenic. He didn't know anything about that.

00:31:46.740 So let's back up for a moment for people. I mean, I think most people listening probably know what

00:31:50.500 the Warburg effect is and who Warburg was. But maybe just give us a moment of setting the stage

00:31:55.780 for what his observation was that now bears his name.

00:31:59.200 Well, his interest was in biochemistry. He was a classical chemist, biochemist in his time.

00:32:06.440 And he began to look at the metabolism of tumors. So he made an observation which was solidified

00:32:15.380 that cancer cells continue to do an ancient fermentation metabolism, even in the presence

00:32:21.620 of oxygen. So this, the Pasteur effect from Louis Pasteur with the yeast was that, you know,

00:32:27.480 yeast will ferment. They evolved. That organism evolved to be able to ferment, get energy in the

00:32:32.460 absence of oxygen. But when, as soon as oxygen came into the presence, they stopped fermenting

00:32:37.720 and they immediately started respiring. They have a system that can do that. So the Pasteur effect

00:32:42.800 was basically the termination of fermentation in the presence of oxygen. That was the Pasteur effect.

00:32:48.180 And it was repeated in all these yeast strains and this kind of thing. And that was a fundamental

00:32:52.780 biochemical advancement, so to say. But Warburg recognized, he knew Pasteur's work very,

00:32:58.820 very well. And then he said, geez, these cancer cells, man, they continue to throw out lactic

00:33:03.120 acid, even in the presence of 100% oxygen. So he grew cancer cells in 100% oxygen. And they were

00:33:10.040 still making lactic acid. So clearly, the Pasteur effect wasn't working.

00:33:14.300 I'll just interject for a moment to explain something to the listener. And we'll probably

00:33:17.220 have a picture of this. But of course, you take glucose to pyruvate in the cytoplasm.

00:33:22.160 Right.

00:33:22.360 And that's a, you know, that yields a couple of units of ATP. And then you have sort of a choice

00:33:27.080 of what you're going to do with that pyruvate. If your demand for ATP is incredibly quick,

00:33:32.420 usually exceeding the capacity of oxygen to get into the cell, you'll make lactate.

00:33:36.860 And that's also relatively inefficient, meaning you don't get that much more ATP. I think you get

00:33:41.160 another two molecules of ATP per unit of pyruvate. But at least you have the advantage of saying,

00:33:46.980 I'm not limited by oxygen. Alternatively, if you, if oxygen is plentiful, and more importantly,

00:33:52.240 if the demand for ATP is not excessive, you can shuttle that pyruvate into acetyl-CoA in the

00:33:58.060 mitochondria, and you can generate over 30 units of ATP.

00:34:01.500 Right.

00:34:01.720 And so what you're saying is there is an observation which said, hey, if I put this cell in the presence

00:34:09.400 of lots of oxygen, it really shouldn't make much lactate.

00:34:13.640 Right. And that's what he finds when you take normal tissue like kidney slices or muscle slices or

00:34:19.040 liver, you'd grow them in 100% oxygen, and they produce minimal, barely detectable lactate.

00:34:26.520 There's always some going to be produced in every tissue, but basically it's very minimal,

00:34:30.840 very minimal. But the cancer cell continues to dump out massive amounts of lactic acid,

00:34:35.940 even in the presence of 100% oxygen. So this was a phenomenon. And he saw this over and over again.

00:34:43.080 It didn't make any difference whether it was a human tumor, a mouse tumor, a rat tumor.

00:34:46.880 They were all doing this same kind of thing. So what he concluded from this was that their

00:34:53.420 respiratory system was defective. Because like you just said, if pyruvate, now that's the end

00:34:59.120 in Meyerhoff pathway going from glucose to pyruvate. Pyruvate is the end of that. So then the opportunity

00:35:06.820 is that the pyruvate would enter into the mitochondria under oxygenated conditions and be fully oxidized

00:35:12.680 to water and CO2. And oxygen is the acceptor of the electrons to form the water. And the carbons

00:35:20.760 are coming from the foods that we metabolized. But the cancer cell was dumping out large amounts of

00:35:26.720 this lactic acid. So why would a cancer cell dump out lactic acid? And it became clear to Warburg

00:35:32.600 through a variety of experiments that the respiratory system was defective in these cells.

00:35:37.460 Let's just clarify that. Many people, when they hear that, we think respiratory system,

00:35:41.820 we think of lungs. What you really mean is the mitochondrial machinery that undergoes what we

00:35:47.100 call cellular respiration. The lungs are bringing in the oxygen and getting rid of the CO2 that enables

00:35:53.140 mitochondria. That enables all the cells and the majority of our cells in the body to perform this

00:35:57.700 very efficient form of energy production, which then frees up the cells to do their sophisticated

00:36:04.420 behaviors. Liver cells do what they do, kidney cells, brain cells. They all do what they do because

00:36:10.300 they have this very efficient energetic system that's working called respiration. The lungs are

00:36:15.780 just the facilitators of the body to get the good air in and the bad air out. So basically,

00:36:22.100 the cancer cell was continuing to produce massive amounts of lactic acid despite the fact that there

00:36:28.060 was all this. So he was then looking at the mitochondria, noticing that there were some

00:36:34.000 defects and these kinds of things. But he wasn't at the level of electron microscopy or this. He just

00:36:40.060 made the- What year? This is in the 1920s? Mostly late 20s, 30s, 40s, all the way up to the 50s. I think

00:36:46.760 he stopped his research maybe in the early 60s. Now, he won a Nobel Prize, didn't he? Yeah.

00:36:51.860 Was it for the description of this phenomenon? No. It was for the discovery of cytochrome C oxidase,

00:36:56.540 which is actually one of the key enzymes in the electron transport chain. How cells generate energy

00:37:00.860 through respiration. So he was nominated other times. And there's still some controversy about

00:37:07.160 how many times he had been nominated for the work on cancer, but never to achieve another Nobel Prize.

00:37:14.200 But he was considered one of the dominant biochemists in the 20th century. And he had very strong

00:37:20.460 ideas and very excellent quantitative measurements for this. A lot of his work was reproduced by

00:37:26.400 dozens and dozens of scientists. So that was the fundamental observation. But he then extended

00:37:32.120 this to the theory that why are the cells are producing all this lactic acid? Because the

00:37:37.860 organelle that is supposed to be involved is defective. This led to a lot of controversy.

00:37:43.260 What do you mean defective? How defective? What do you mean? So much later, Pete Peterson from Johns

00:37:48.120 Hopkins had done a magnificent job in collating all this information. And he found that in every kind

00:37:55.120 of a cancer cell, no matter what kind of it is, there was some defect in the number structure or

00:37:59.180 function of the mitochondria. And it could vary. So some cancer cells have very few mitochondria,

00:38:03.840 but they look normal, very few of them. Other tumor cells clearly have a lot of mitochondria,

00:38:09.200 but they look abnormal. So whatever it was, it was something to do with an impairment of the

00:38:13.620 respiratory system within the cell. And if the cell can't generate energy through normal respiration,

00:38:19.280 then it has to ferment. There's no other way they can get the energy. So it became the Warburg effect,

00:38:26.000 which everybody talks about, is one of the biggest problems in this whole thing. Because Warburg in

00:38:31.920 his paper clearly said that aerobic glycolysis, or what they call the Warburg effect, is a secondary

00:38:37.180 problem that's subjected to many, many variances in the environment. But everybody focuses on this.

00:38:43.400 He said the real issue is the damage to the respiration. And everybody says, no, respiration is normal

00:38:47.560 in cancer cells. And why would they say it's normal? Because they started doing cells in culture

00:38:52.860 rather than looking at the tissues themselves. And once you start doing culture work, you're taking

00:38:58.200 cells from a tissue and separating them and growing them as if they were microorganisms in a culture dish.

00:39:04.820 Well, this changes everything. They're no longer connected to each other. They're growing in

00:39:08.120 some artificial fluid. And they're doing things that they sometimes do and sometimes not do in the

00:39:13.820 real world. So you make a lot of assumptions about things based on a system that itself is

00:39:20.020 artifactual. So let me ask a couple of technical questions. Obviously, measuring the amount of

00:39:26.260 lactate or hydrogen ion that's produced is a way to give us an indication of how much anaerobic

00:39:31.420 metabolism is taking place. If you're not in cell culture, how do you quantify the amount of aerobic

00:39:40.080 respiration? You look at the amount of oxygen consumed and the amount of lactic acid produced.

00:39:45.660 So if you're doing aerobic respiration, you're consuming a lot of oxygen and producing very

00:39:51.600 little lactate. And then you can quantitate the amount of ATP being produced per milliliter of

00:39:58.440 oxygen that you consume. And according to this, this can vary from anywhere from seven ATP units to nine,

00:40:05.240 depending on the system. But it's, you know, Warburg used the number seven based on his data

00:40:09.860 at that time. So you could calculate the total amount of ATP being produced in the cell based

00:40:14.380 on its oxygen consumption and its lactic acid production.

00:40:17.280 And Warburg, did he ever do this in situ?

00:40:20.040 Yes. He did it in slices and then he did it in cell culture as well. So he created some of his own

00:40:26.380 problems as well, switching from one to the other. The concern that we have now is that many cells in

00:40:34.120 culture look like they're consuming a lot of oxygen. And they're making lactic acid, but they're

00:40:39.380 consuming a lot of oxygen. So like you said-

00:40:41.880 Suggesting that they're doing both, which is still a bit odd.

00:40:44.340 Yeah, right. Well, that was Sidney Winehouse's argument. His argument was the cancer cell needs

00:40:48.080 so much energy that respiration by itself can't be sufficient. So they have to ferment and respire

00:40:52.880 at the same time. And that made everybody feel that, yeah, Warburg was wrong. They do have good

00:40:59.180 respiration, but they just need so much more energy. They need to ferment at the same time.

00:41:03.620 But the work from Pete Peterson showed that they have defective respiration. So, I mean,

00:41:07.540 they have defective mitochondria, structure, number, and function, besides many other studies

00:41:11.260 have shown. So you know that they can't be doing oxidative phosphorylation or respiration because

00:41:16.420 the very organelle that is needed for that is deficient in some way. And that could be many

00:41:20.800 different ways. As I said, there's no one, all cancer cells, all cancer cells have a defect in

00:41:25.440 respiration. How that defect came about can vary from one type of cancer to another. So one has to

00:41:31.360 recognize that. So not every cancer cell will have the exact same defect in respiration. In the

00:41:37.060 mitochondria, some will have very few mitochondria. Okay. So they just don't have quantitatively enough

00:41:41.960 organelles to do respiration. But what seems to be there seems to be functional to partially

00:41:48.120 functional. Other cells, as I said, are loaded with mitochondria, but when you look at them,

00:41:52.700 they're morphologically abnormal. So structure dictates function. In biology, we know that structure

00:41:58.620 dictates function. So if the structure of the organelle is abnormal, you know that the function

00:42:03.200 of that organelle is not going to be normal. And is the idea that those mutations were acquired?

00:42:09.100 Oh, I wouldn't call them mutations. They would call them defects. Now you can have-

00:42:12.420 In other words, the genome is unaffected in some of those cases?

00:42:15.100 Yes. We've done that. We sequenced the entire genome of five different independently derived

00:42:20.240 cancers from mouse, all derived from different origins. And we didn't find a single genetic abnormality,

00:42:27.100 what we call pathogenic, where the mutation would actually have an effect on a function.

00:42:32.220 And we didn't find a single one. So that told-

00:42:35.660 So let's take, maybe take a step back and for the listener again, we'll go over some of the basics

00:42:40.220 of genetics. Because I think that for many people, there's an understanding that, I mean, by definition,

00:42:46.280 a cancer has a mutation that renders it incapable of listening to normal cell signaling. Do you have a

00:42:53.180 sense broadly of what amount of human cancers arise from germline mutations rather than somatic

00:42:59.740 mutations? It's obviously very small, but I don't know what the number is.

00:43:02.840 Well, they say it's about five to six percent.

00:43:04.980 Oh, it's that high. Okay.

00:43:06.140 You know, and you hear about them, the BRCA1, BRCA2, relief from any P53, you know- 0.98

00:43:12.060 Lynch syndrome, et cetera.

00:43:13.060 Yeah, yeah. But when we looked into those so-called inherited risk, we call them inherited

00:43:18.080 risk factors. None of them have ever been 100% penetrant, which means that every person having

00:43:23.440 that gene must express-

00:43:24.540 They're not purely deterministic.

00:43:25.900 Yeah, they're not deterministic. And as Warburg said, there are many secondary causes of cancer,

00:43:30.580 but there's only one primary cause. The primary cause is the damage to the respiratory system.

00:43:35.720 So if the inherited mutation damages the respiratory system of the cell, the probability of cancer

00:43:41.120 is a real possibility. So because everybody who has leaf from many tumors or BRCA1 tumors or

00:43:47.940 whatever, they're all fermenters. So the fermentation metabolism is there in every cancer.

00:43:54.700 But there are some people that have the exact same mutation that the other person has, but they

00:43:58.800 never develop a tumor because for whatever reason, in that person, that mutation did not damage the

00:44:04.620 respiration. That could be an environmental suppressive effect or another gene in the genome that

00:44:10.220 prevents the inherited mutation from damaging the respiration. We don't know that. So we only know

00:44:16.680 that you don't get cancer if your mitochondria remain healthy. That's what we know. So that's

00:44:22.060 an important, because that goes back to the prevention issue. You know, how do you prevent

00:44:25.140 cancer? You prevent cancer by keeping your mitochondria healthy. How do you do that? Well, you avoid,

00:44:30.200 if you can avoid those risk factors, mostly from the environment, like viral infections,

00:44:36.240 intermittent hypoxia, radiation exposure, carcinogenic exposure, all these different things.

00:44:41.460 Every one of those things can damage respiration in a population of cells, then leading to cancer.

00:44:45.740 Because we know of no cancer that has normal respiration. But when you grow them in culture,

00:44:49.860 people say, yeah, they have normal respiration. They're taking in oxygen. So therefore,

00:44:52.800 Warburg's wrong. But when you look at the structure in the vivo, and you look at the tissues, and you

00:44:56.920 look at the actual architecture of the tissue, invariably, you find damage to the respiration,

00:45:01.060 damage to the structure and function of mitochondria. So what the field has done is put more credibility

00:45:06.720 into the results from cell culture work than into the actual tissues that people see and look under

00:45:10.860 the microscope and look at. Because the Warburg effect was largely forgotten for many years

00:45:15.000 after his initial observation, right?

00:45:17.120 Yeah. A lot of what he did was forgotten. And Pete Peterson was one of the few guys that kept

00:45:21.660 the fire burning. Because as I said, when Watson and Crick discovered the DNA as the origin of the

00:45:28.300 genetic material, but it wasn't only them. There was a whole group of other people that were doing it.

00:45:31.480 They just weren't acknowledged as much. Yeah. And then the field ran off into that. And they also

00:45:37.260 knew that there were chromosomal abnormalities in some cancers. So it made clear that, hey,

00:45:41.480 you know, these genomic defects in the tumor cells are likely the real origin of the disease.

00:45:47.460 So the whole field more or less shifted away from the traditional biochemical analysis to the more

00:45:52.460 molecular biology analysis. And therefore, you find more and more mutations, more and more genetic

00:45:58.640 defects, and all these kinds of things, leading people to believe that these were the causes of

00:46:03.880 the disease. And, you know, a lot of really nice experiments were done where they would introduce,

00:46:08.760 you know, mutant virus particles into cells. And they would integrate into the nuclear genome.

00:46:13.920 And then you'd see the cancer cells lose, become transformed into a neoplastic kind of a cell,

00:46:19.700 making, giving the appearance that this was a cause effect. That if I, they didn't realize that

00:46:25.540 those same viruses went into the mitochondria and blew out the respiration. So that wasn't even

00:46:30.460 considered as possible. But if the viruses are doing that, presumably they're integrating into the

00:46:35.420 genome? Yeah. Well, they would do it both ways. They can do it a lot of different ways.

00:46:38.520 So sometimes the viruses actually infect directly into the mitochondria. They produce proteins in

00:46:43.240 the mitochondria that screw up the electron transport chain. Other times the viruses integrate

00:46:47.840 into the nuclear genome, producing a protein product that then disrupts the mitochondria.

00:46:53.560 Either way, the mitochondria disrupt it, whether if it's a direct effect of the virus replicating

00:46:59.300 inside the organelle, or it's an effect of a product produced by the virus that then goes

00:47:03.720 disrupts the organelle. And this is what we're finding for the majority of these situations.

00:47:09.540 So even the herited mutations that we look at, they disrupt mitochondrial function. And if they

00:47:14.400 disrupt mitochondrial function, you're at risk for developing a neoplasm in that particular

00:47:19.040 population of cells. There are some cancers that don't follow that, correct? I mean, aren't there

00:47:24.600 some cancers that have normal mitochondria? We haven't found any, because the evidence for that

00:47:30.080 is that they're all fermenting. We haven't found a cancer that doesn't ferment. So if the cancer is

00:47:34.660 fermenting, it's obviously not respiring. If its respiration would be normal, it shouldn't be

00:47:40.520 fermenting. As a matter of fact, Dean Burke did this kind of a study way back in the 50s. He went and

00:47:45.400 looked at various kinds of hepatomas, because there was an article that was published to say that there

00:47:49.860 was this very low, slow-growing hepatoma that did not ferment, which was directly related to your

00:47:56.160 question. But Burke, who was at the head of the NCI at the time, studied these things in massive

00:48:01.280 detail and was able to show that the slowest-growing tumor did have a significant elevation of lactic

00:48:09.200 acid production over a normal cell. But you had to look at it really carefully and do the experiments

00:48:14.100 over extended periods of time. So even the slowest of the slowest-growing tumors, guys that would

00:48:19.100 be maybe considered benign, were still making lactic acid.

00:48:23.760 Another interesting thing was the crown gall tumors in plants. This is another interesting...

00:48:30.680 Plants have cancer, but they don't metastasize. They just grow these tumors. And people back in

00:48:35.000 the 30s were testing Warburg's theory in these plants, and they all had damaged respiration.

00:48:39.920 They were fermenting, just like the mouse tumors.

00:48:42.520 When you say respiration, you mean photosynthetic respiration?

00:48:45.520 No. No. Plants have both. Plants can get energy from chloroplasts to build carbohydrates.

00:48:50.220 But they also have mitochondria.

00:48:52.320 Oh, I didn't realize that. So their carbon fixation obviously comes from photosynthesis.

00:48:56.120 Yeah. Yeah.

00:48:57.080 But when they make, you know, their equivalent of starch.

00:49:00.180 Yes. So they will burn their own fuels to generate respiratory energy. But they also have 0.64

00:49:06.700 dysmorphic cell growth, and they've called these crown gall tumors. You see them sometimes on the

00:49:11.260 side of trees and things. So people back in the day analyzed the biochemistry of these things. And

00:49:16.800 they also found that they were following Warburg's metabolic profile. But they didn't metastasize.

00:49:23.060 And the reason they don't metastasize is they don't have an immune system. So, and it turns out that

00:49:28.500 from our work and the work of others, the metastatic cell is actually part of our immune system.

00:49:33.120 So macrophages and leukocytes, these are the cells that have the genetic capability of moving around

00:49:39.080 the body, entering into tissues. This is what they do. Plants don't have that. Plants don't have that

00:49:44.220 kind of an immune system. So they don't metastasize. They grow in place. But humans and other animals,

00:49:50.880 of course, that have these cells of the immune system. Therefore, they can get metastatic cancer.

00:49:55.940 So before we get to that, because I do have a number of questions about that topic,

00:49:59.420 another argument that's been proposed for the Warburg effect is the need for cellular building blocks.

00:50:06.040 The other thing that the tumor is doing above and beyond its non-tumorous cellmate is growing.

00:50:12.800 And although not necessarily faster than a regular cell, it certainly grows in a less regulated way,

00:50:17.740 and therefore it's going to proliferate. So van der Heiden and I think Lou Cantlie and Craig Thompson

00:50:23.760 wrote that paper in 2009 that I'm sure you're familiar with. It was a science paper, I believe.

00:50:28.800 And they proposed this other explanation, which was, look, it's not just an energetic thing. In fact,

00:50:34.960 I don't recall if they said it's not just or it's not even about the energetics. But the point here was,

00:50:40.140 this is where you get building blocks to make cells grow. Do you think it's possible that both of

00:50:44.800 these are correct? Yeah. Well, you know, in the process of upregulating the Emden-Meierhoff

00:50:50.760 pathway, you are going to get the carbons for building blocks. At the same time, you're going

00:50:54.960 to get some energy. Now, through the pyruvate kinase system. However, this is very interesting.

00:51:02.440 Now this is, but they deviate from the path from Warburg's theory in saying that respiration is

00:51:07.560 normal. Okay. They think there's nothing wrong with the mitochondria. Okay. They've said that many

00:51:11.740 times. Craig Thompson has said this. You have to ignore a massive amount of evidence to make those

00:51:16.900 kinds of statements. You just have to ignore everything that Pete Peterson has done, which

00:51:20.720 is a life's work showing that the mitochondria, but he doesn't mention that. They don't discuss

00:51:26.560 Pete Peterson's massive amount of evidence. But you're right. In order for a cell to grow,

00:51:31.120 you need a lot of building blocks. And you need carbon. Where's the carbon coming from this?

00:51:34.900 And it's coming from both the pentose pathway and the glycolytic pathway. And it's also coming

00:51:40.000 from glutamine. So these cancer cells are sucking down glutamine. So you're getting the amide nitrogen

00:51:45.380 to form the nucleotides. You're getting the glutamate that then goes into anaplerosis in the

00:51:49.840 TCA cycle. So between glucose and glutamine, you are getting all of the building blocks that you need

00:51:55.520 for rapid cell division. But where's the energy coming from? Okay. Without energy, nothing grows.

00:52:00.700 Nothing can live without ATP. So where is the energy coming from? And this is our thing. So we,

00:52:06.920 myself and Christos Chernopoulos in Hungary, I proposed this a long time ago on a purely theoretical

00:52:14.380 basis, having been convinced that Warburg was right, that the respiration of all cancer cells

00:52:20.700 is damaged to some extent. So if that's the case, the Warburg effect was only the glucose part of the

00:52:27.400 puzzle. It wasn't the glutamine part of the puzzle. So now with our new information, we know that most of

00:52:32.880 the ATP in the cancer is coming from substrate level phosphorylation in the mitochondria, which is

00:52:38.020 disconnected from oxidative phosphorylation. So what we have now is the missing link in Warburg's

00:52:43.640 basic theory. So explain what SLP is. Substrate level phosphorylation is the production of ATP when

00:52:50.920 you move a phosphate group from an organic substrate onto an ADP molecule. So it's an ancient way of

00:52:57.200 generating energy. In other words, it's an organic molecule that's an electronic septor rather than

00:53:02.060 oxygen. Right. So instead of going through the electron transport chain where you use NAD,

00:53:07.720 NADH, NADP, NADPH as electron transporters- Well, electron donors.

00:53:13.020 Electron donors. You can do a very quick trick where you take an ADP and restore it, meaning it

00:53:20.160 has two phosphates. You restore it to an ATP by using an organic molecule to donate a phosphate.

00:53:25.120 Well, for substrate level phosphorylation. Yes. Yes. So succinyl-CoA has a phosphate group on a

00:53:31.640 serine inside the protein itself. And that phosphate group is then donated to ADP, sometimes GDP, make

00:53:38.660 GTP, both. Depends on the situation. But in cancer cells, it's ATP. So you're moving phosphate groups

00:53:44.840 from an organic substrate onto the ADP as the acceptor. And you can generate massive amounts

00:53:51.740 of energy from that process, which can replace the level of lost energy from oxidative phosphorylation.

00:53:57.180 And does that occur inside the mitochondria, inside the inner matrix?

00:54:01.180 Yes. Yeah. It's in the matrix. So you're going to be blowing out a lot of, you're going to make a

00:54:04.860 lot of AT. It's going to just replace. In the normal cell, you're making most of the ATP from

00:54:09.100 oxidative phosphorylation. But in the cancer cell, you're making most of it from substrate

00:54:13.420 level phosphorylation. Inside the same organelle. Why don't our cells do this under demand? So if

00:54:18.980 we jumped up and down and did 25 burpees right now, we would very quickly exceed our oxidative

00:54:24.280 capacity for respiration. And we'd start making a bunch of lactate. Why aren't we also undergoing SLP?

00:54:29.560 Well, we do. In the heart muscles, they do. On various cardiac restrictions and things like that,

00:54:35.600 a lot of this has been worked out in the heart. So it does happen. I mean,

00:54:39.100 we do do substrate level phosphorylation, but it only can be done for short periods of time. It

00:54:44.040 can't be done extensively. You can't replace oxidative phosphorylation under normal conditions

00:54:48.780 with substrate level phosphorylation. You hold your breath, you're going to be able to survive

00:54:52.900 for a certain period of time. Lactic acid builds up. I mean, this was shown by Hoshkatska when he did

00:54:58.840 some incredibly interesting experiments trying to hold various aquatic animals underwater and looking at

00:55:05.020 the metabolic changes that occurred. So seals, porpoises, turtles, you know, these kinds of

00:55:10.460 things. He strapped them to a board, held them underwater, and then he would measure all these

00:55:14.360 metabolites in the bloodstream. Now, these were animals that actually could live underwater. If

00:55:18.480 they did it to us, we'd all be dead, right? We couldn't live that long, but five minutes at the

00:55:21.740 most. But these animals could live 10, 15, 20 minutes being held underwater. And they weren't

00:55:27.360 breathing. Of course, now they were stressed out because they were strapped to a board. But the bottom line

00:55:31.520 is he started measuring all these metabolites in the bloodstream. Lactic acid goes right through the

00:55:35.260 massive amount. I'd expect that, right? So, and succinic acid. Succinic acid is another.

00:55:41.300 So, succinic acid is part of the, in the electron, in the TCA cycle, is a powerful stimulatory towards

00:55:48.640 oxidative phosphorylation. And it was being dumped out into the circulation. So, it wasn't being oxidized.

00:55:55.360 So, he claimed that it was amino acid fermentation that was doing this. So, the body was grabbing amino

00:56:00.900 acids and metabolizing them and generating energy through substrate-level phosphorylation. Well,

00:56:07.260 it turns out the cancer cell is doing this in a massive amount because they don't have the

00:56:10.460 oxfos. So, you look at cancer cells and they're dumping out succinic acid. And succinic acid,

00:56:15.240 it stabilizes HIF-1-alpha. So, you can continue to up the transcription factors for drive and

00:56:20.260 fermentation. So, this whole thing is just a massive shift from oxfos to substrate-level

00:56:26.500 phosphorylation.

00:56:27.220 Does creatine phosphate fit into that SLP pathway or is that totally separate?

00:56:31.080 No, I'm not sure about that. It could be a source of the phosphate groups,

00:56:34.860 but I haven't looked into that. Dominic may know a lot more about that than I do.

00:56:39.560 So, when you go back to sort of, there's an undercurrent here to what we're talking about,

00:56:44.140 which is the view that you hold is the minority view today, it sounds like.

00:56:49.740 Just, it's only, it's just a matter of time. Okay.

00:56:52.480 Why do you think that is? What do you think is the, I mean, I know people want to come up with

00:56:58.200 conspiracy theories and that's sort of one of the things about social media that I find

00:57:01.620 frustrating is people always want a conspiracy theory to be the explanation. Like, oh, the drug

00:57:06.380 companies don't want this to be true or something. I find those things hard to believe. Do you think

00:57:10.460 there's a better explanation for why these hypotheses are not being investigated with the rigor that

00:57:18.400 maybe they should be? Well, you have to look at the discipline of the individuals that are working

00:57:22.060 on the project. Okay. So, if most of the people doing cancer research are molecular biologists,

00:57:26.820 which they are, you have that perspective on the nature of the problem. So, you don't look at

00:57:31.840 respiration directly. You look at gene expression profiles that may be directly or indirectly related

00:57:37.220 to that. And then you make claims about what's going on. So, if most of the people are of a

00:57:42.240 discipline that says that genes are changed and not looking at the actual consumption of oxygen

00:57:48.380 and like production of lactic acid, not looking at what Warburg actually looked at, then you have

00:57:52.840 a very different explanation for what's happening. So, a lot of people today look at, use the seahorse

00:57:58.660 instrument to measure oxygen consumption. And when you put cancer cells and tumor cells,

00:58:03.760 normal cells into a dish, they're all taking up oxygen similarly. And therefore, Warburg must be

00:58:08.600 wrong. Warburg also said that tumor cells and normal cells will take, some will take up oxygen at the

00:58:14.720 same rate. Except the tumor cell is uncoupled and the normal cell is not uncoupled, which means that

00:58:19.400 the oxygen uptake in the tumor cell is not linked directly to ATP production. People ignore that.

00:58:25.340 So, they just don't. And some of the most beautiful experiments-

00:58:27.920 How would one measure that? ATP is very tricky to measure, ATP production.

00:58:32.360 No, ATP can be measured. The problem is, is that what's the origin of it?

00:58:37.000 Well, that's what I mean. Isolating. So, let's say you have a tumor cell and a non-tumor cell,

00:58:41.940 and they're both taking up lots of oxygen as measured by, you know, calorimetry. And one's

00:58:47.680 producing a bunch of lactate. But how can you tell if the cancer cell is taking up oxygen and

00:58:54.360 not making ATP? Well, if it's taking up oxygen, well, if it doesn't make ATP, it's dead. All right,

00:59:00.880 so- Sorry, if it's not making ATP commensurate with its oxygen consumption.

00:59:05.980 Well, sometimes you look at that and you'd say, well, look at the oxygen consumption is,

00:59:09.500 the ATP production is commensurate with oxygen update.

00:59:12.700 Yes.

00:59:13.160 Okay.

00:59:13.880 That would be coupled, wouldn't it?

00:59:15.760 Well, as long as it's not producing lactic acid or succinic acid. Okay.

00:59:19.600 So, I'm a bit confused. Why couldn't it do both? Couldn't a cell undergo anaerobic metabolism,

00:59:26.200 make ATP that is accounted for by the amount of lactate that's produced, but similarly take up

00:59:31.720 oxygen and in a coupled fashion make ATP there?

00:59:34.820 That's an important point because a lot of people stumble on that. The problem with that is that

00:59:40.280 when you're looking at the ATP production coming out of the mitochondria, it's not always easy to

00:59:46.760 know whether it's from a coupled, generated by a coupled mechanism where the oxygen is in fact

00:59:53.480 linked to the ATP through F1, F0 ATPase, or whether it's coming from mitochondrial substrate level

00:59:59.960 phosphorylation.

01:00:01.380 Ah, got it.

01:00:02.420 So, you can't, there's not, it's not easy to do the mass balance of this many moles of oxygen were

01:00:07.340 produced or consumed and this many moles of ATP were produced. You can't do that math.

01:00:13.860 Well, Warburg did that, but he was looking at-

01:00:16.080 But he didn't know about SLP, right?

01:00:17.940 Well, lactic acid production, the production of ATP at the pyruvate kinase is substrate level

01:00:24.060 phosphorylation, but it's cytoplasmic.

01:00:26.180 Yes, yes. It's not mitochondrial.

01:00:27.860 He did not know, he couldn't have known because the very systems that were, they didn't come out

01:00:32.980 until the 50s, 60s, that we knew that there was another form of ATP production inside the

01:00:38.160 mitochondria. What people have failed to realize is that they consider, every biochemical textbook

01:00:46.200 says we only get 2% oxygen coming out of the mitochondria through a substrate level

01:00:51.000 phosphorylation, just like we get from the cytoplasm. But for cancer cells, people say, oh,

01:00:56.800 you can get a lot more ATP from the cytoplasm. But not thinking you can upregulate the same

01:01:01.580 phenomenon inside the mitochondria. As a matter of fact, we think that substrate level phosphorylation

01:01:07.100 in the mitochondria is far greater than the amount of ATP produced in the cytoplasm. And that's because

01:01:13.560 others can't, and others, a number of people have found that the PKM2 isoform of pyruvate kinase

01:01:19.480 doesn't make much ATP. It makes a buttload of lactic acid, but it's not linked to the ATP

01:01:24.720 production. So therefore, they have to say respiration is normal because the cell is making

01:01:29.120 so much ATP. But if Otto Warburg is correct, and all of the structural biochemistry is correct,

01:01:36.340 the mitochondria can't be making oxygen from oxidative phosphor. It can't be making ATP from

01:01:40.460 oxphosphor. It can't be because the structure of the organelle is defective. So where the hell is

01:01:45.580 all that damn ATP coming from inside that organelle? And then when you look at the data that we have, 0.99

01:01:52.100 and glutamine is being consumed in massive amounts. So it's got to be coming from substrate level

01:01:57.940 phosphorylation. What is the fundamental structural defect in the mitochondria? Which is interesting.

01:02:02.200 I'd never thought until this discussion about the possibility that you could have a completely

01:02:07.820 normal mitochondrial genome and just have structural defects. And then of course, obviously you can have

01:02:13.520 genetic abnormalities that lead to protein productions. They create structural problems.

01:02:17.880 But in the case of the former, perfectly normal genome.

01:02:22.100 Mitochondrial DNA genome.

01:02:23.380 That's right. Mitochondrial.

01:02:24.560 Yeah.

01:02:25.000 But you now have a defective. What is the actual physical defect?

01:02:29.120 In the structure, the number structure. This is the, it can happen in many different ways.

01:02:33.800 For example, if a carcinogen enters into the mitochondria, they cause a lot of oxidative stress.

01:02:40.220 And what we found in our massive studies, this is how we got onto the mitochondria, knowing that

01:02:45.760 Otto Warburg was in fact correct. I mean, at first I was, didn't know what the hell was going on like

01:02:49.980 anybody, like everybody else. But when we found no mutations in the mitochondrial DNA, and we knew

01:02:56.380 these cells were fermenting because they were making a lot of lactic acid. Then we started looking at the

01:03:01.320 lipids inside the mitochondrial lipidome. We call it the lipidome. And we have found that cardiolipin,

01:03:08.860 the signature lipid in the inner membrane is defective in all the tumor cells that we've

01:03:12.720 ever looked at. So that tells us right there that there's a problem in the function. And then we

01:03:17.260 link that to abnormalities in Oxfos. So clearly lipids are abnormal. That would affect the function

01:03:23.880 of the proteins of the electron transport chain. Therefore, you're not going to generate the

01:03:28.680 amount of ATP through oxidative phosphorylation because the very lipid and protein structures are

01:03:36.320 abnormal. And you can't produce the amount of ATP. So that supports Warburg knew that there were many

01:03:43.920 problems in the mitochondrial function that would then force the cell into fermentation.

01:03:48.820 So what did they ferment? They ferment lactic acid and succinic acid. What are the fuels for that?

01:03:55.460 It's glucose and glutamine. So glucose and glutamine are ultimately the fuels that drive the cancer.

01:04:00.420 And they drive it through a process of substrate level phosphorylation occurring in the cytoplasm

01:04:05.880 where they can build a lot of metabolites for growth and also through the pathway called

01:04:10.460 glutaminolysis. Now, one can't render glucose zero, meaning there's no dietary or pharmacologic

01:04:18.800 intervention that could reduce glucose levels to zero. Are there any that could do that with glutamine?

01:04:24.580 Or is it similar? Let me address the glucose issue. We can't get to zero,

01:04:28.660 but we can get damn close to it. All right? So we have people, published papers,

01:04:34.140 people who have gone powerful therapeutic fasting only, and then given large injections of insulin.

01:04:39.240 Sure. And they've got to below one millimolar.

01:04:41.060 Yeah, 0.5.

01:04:43.160 But sustainably, it's very difficult to be below about three millimolar, right?

01:04:47.620 Right, right. But here's the situation. The problem is, is when you do that,

01:04:51.400 you go into calorie restriction, restricted ketogenic diets,

01:04:54.000 you already are lowering the blood sugar to a significant degree. And what we found is that

01:04:59.420 glucose transporters actually get upregulated in the normal cells when you start doing this.

01:05:04.300 So the normal cells become glucose hungry. And they become direct competitors now with the

01:05:09.200 tumor cell that absolutely needs the glucose, because the normal cells can burn the ketones and

01:05:13.100 stay alive. The tumor cells can't burn the ketones because they're mitochondria defective.

01:05:17.380 So you need a good mitochondrial system to burn ketones for energy. So what we do by calorie

01:05:22.860 restriction and keep restricted ketogenic diets is we make the normal cells glucose hungry,

01:05:27.680 and we transition them over to ketones, keep them alive, but they're still glucose hungry.

01:05:32.860 And they are now competing directly with the tumor cells that absolutely have to have the glucose.

01:05:37.520 It's interesting because clinically, we don't see that, right? So clinically, when we put

01:05:40.800 most people on a ketogenic diet, or a calorie restricted diet, in the short run,

01:05:46.140 they actually become physiologically quite insulin resistant. Meaning when you challenge them with

01:05:51.900 glucose, they have a paradoxical rise in glucose and insulin that's overcome by refeeding them with

01:05:58.140 carbohydrates for three or four days prior to the glucose challenge. And the offered explanation is

01:06:04.300 that during a period of starvation and or carbohydrate restriction, the muscles, which are obviously the

01:06:10.260 dominant sink for glucose, basically become resistant to insulin, not in a pathologic way,

01:06:18.300 but rather in a way to allow the brain to have access for the remaining glucose.

01:06:22.820 Well, if you do it in acute systems like that, rather than the chronic changes that we talk about,

01:06:27.460 you can get those kinds of an effect. Generally, calorie restriction makes the body super insulin

01:06:33.700 sensitive.

01:06:34.120 Yeah, it's interesting. This is something I've struggled with because I was on a ketogenic diet

01:06:39.260 for three years. And at the end of that period of time, I went up to Stanford and did an insulin

01:06:45.940 suppression test, which is, along with the euglycemic clamp, really the gold standard for

01:06:50.440 measuring insulin sensitivity with Gerald Riven, the late Gerald Riven. And Jerry was just interested

01:06:56.400 in my physiology. It was like, wow, you're kind of a weird guy. You're on this bizarre ketogenic diet.

01:07:01.240 Hadn't studied it. He did at the time have a publication of about 400 non-diabetic subjects

01:07:09.760 who he had put through the insulin suppression test. The way this test works for the listener

01:07:13.600 is you take an individual, you hook them up to two intravenous lines, one that puts glucose in,

01:07:19.500 one that puts insulin in. And over a six hour period of time, you follow a protocol of injecting

01:07:26.060 glucose and insulin. And after about six hours, the glucose level reaches a steady state level

01:07:32.080 referred to as the SSP or steady state plasma glucose level. And the higher that is, the more

01:07:38.420 insulin resistant you are said to be, the worse you are at glucose disposal. The lower that is,

01:07:43.960 the more efficient you are able to dispose of glucose. So, and that number, the SSPG correlates to

01:07:50.180 the one over the M value, which is the Y-axis intercept on the U-glycemic clamp. So anyway,

01:07:56.640 so I went to Stanford one day.

01:07:58.200 Well, let me, let me, why, why would you inject glucose and insulin? If you were on a ketogenic

01:08:02.920 diet, you'd be already, and you were to take glucose, your insulin levels would already go up

01:08:07.660 to the maximum physiological. So you're actually giving too much insulin in a situation like that.

01:08:12.120 Well, so this was part of the issue, right? We didn't know what to do because the protocol is

01:08:16.480 all developed around people, not on a ketogenic diet. These are all people eating a standard diet.

01:08:21.460 But what you've, what you're alluding to is what we discovered very quickly. So again,

01:08:25.120 this is supposed to be a six hour test. And when you looked at, and I looked at the data before we

01:08:30.580 did this to get a sense of what the parameters were of the 400 non-diabetics that they had done this on

01:08:37.280 the most insulin sensitive person ended up having an SSPG of about 79 milligrams per deciliter,

01:08:45.320 meaning the lowest that anyone's glucose got following this protocol was 79 milligrams per

01:08:51.700 deciliter, which perfectly reasonable. And the highest was, I don't recall this, but we could

01:08:58.220 look up the paper, but I think it was somewhere in the vicinity of 200, 300 milligrams per deciliter.

01:09:03.140 So that's a person who is functionally a diabetic. And even though they're quote unquote, you know,

01:09:08.140 normal, their A1C was less than 6.5. They're very soon to be a diabetic. And of course,

01:09:12.140 when you do this on people with type two diabetes, they're all very, very high.

01:09:15.920 So we're doing this test where they're sampling glucose levels every 30 minutes. And within an

01:09:21.740 hour, meaning after just the first, second, third sample, it was clear my glucose was going down

01:09:27.540 very quickly. So they said, okay, we're going to back off on the insulin to your point at 90 minutes.

01:09:34.580 And I have to go back and look, cause I have all the data. I could be wrong. Maybe it was a little

01:09:38.040 longer than that. I think it was about 90 minutes. They basically turned the insulin off. Now at this

01:09:42.140 point, my ketone started to go down. I think between the 90 minute and the two hour mark,

01:09:48.700 it got really bad, really quick. And my ketones at this point had gone from, I don't remember,

01:09:54.360 somewhere between two and a half, maybe three millimolar down to less than one millimolar.

01:09:59.160 And they said, you know, we're going to stop the test now because your glucose is in the

01:10:04.780 forties. I believe I was at about 48. Yeah. No ketones. You're going to go

01:10:08.540 unconscious. You've got to be careful. Yeah. So in the end, I almost did go unconscious. And

01:10:12.880 the last thing I sort of remember was the profound perspiration that came over me, which is very

01:10:19.880 different from the perspiration you experienced like on a day like today in Boston, where it's hot

01:10:24.040 and you're sweaty. It's, it's not that type of a perspiration at all. It felt like I was in a shower

01:10:29.360 and I began shaking and probably was about to have a seizure. And then they went. So the last

01:10:36.860 blood glucose, I think they, I, they got on me was about 31 milligrams per deciliter. And when they

01:10:41.880 were injecting the dextrose, the D50, I was conscious enough to realize the IV had infiltrated.

01:10:48.660 So all I felt was the most ridiculous burning sensation in my antecubital fossa, because I

01:10:54.120 realized the dextrose was not getting into my... Why you put yourself in situations? 1.00

01:10:57.600 I'm an idiot. I mean, the worst part of that story is I didn't, I would never do any of that 0.99

01:11:01.520 stuff. When I came back to life, I, uh, I had a huge, huge infiltrated IV in my right, in my left

01:11:09.580 antecube. I took a picture of it and I sent it to my wife and who I didn't even tell that I had

01:11:14.460 flown up to San Francisco that day. I think I was just like, you know, I travel so much that like

01:11:18.040 I could be gone for a day. She wouldn't even know it. And I was like, Hey, check this out. And she's

01:11:21.940 like, where are you? And I was like, Oh, I'm up at Stanford today doing such and such. She's like,

01:11:24.860 what? You just about died. And like, you gotta, you gotta, if you're going to die, I mean,

01:11:30.240 you're an idiot, but you've got to tell me in advance where you're going to be when you die. 1.00

01:11:33.720 Yeah. Well, I mean, our goal is, is not to try to kill ourselves. It's just kill the tumor 1.00

01:11:38.220 cells and make the rest of it. Okay. So my long winded story there was to illustrate a point.

01:11:42.160 I turn out to be an exception to that rule. So, and I did this with oral glucose tolerance tests as

01:11:48.100 well. And I never had that physiologic insulin resistance. In other words, I seem to be one of the

01:11:52.380 people for whom what you're saying seems to be correct chronically, which is whenever I'm on a

01:11:57.480 ketogenic diet, my glucose disposal is remarkable, but now putting on my sort of your insulin set,

01:12:04.640 you're very high insulin. My muscles become very insulin sensitive, but without the refeeding of

01:12:11.420 carb. Yeah. Yeah. What I noticed though, is clinically, I see so many patients for whom that

01:12:16.340 is not the case. If I do an OGTT, an oral glucose tolerance test on a patient in a ketogenic diet,

01:12:22.860 I feel like, and again, I think other physicians listening to this will have to weigh in with their

01:12:27.580 opinions. I feel like 70% of them fail the OGTTs and look like they have diabetes or are, or very

01:12:35.260 soon to. However, if when on the repeat OGTT, you just say, look for the three days prior to the test,

01:12:41.780 you're going to eat two potatoes a day. They pass with flying colors. In other words,

01:12:46.460 they show that they are indeed very insulin sensitive, but they need to be primed a little

01:12:50.920 bit. So my point though, is if that's the case, if the 70% of patients or whatever the number is,

01:12:57.380 they wouldn't actually benefit from this effect, right? Because they'd be walking around and not,

01:13:04.340 you know, they'd be, the muscles would be selectively not consuming that glucose.

01:13:07.780 Unless you can get the blood sugar down. Like, as I said, we're, we're experimenting now. Because

01:13:12.780 don't forget, our goal is to starve the tumor cells. This, I mean, we're singularly focused on

01:13:17.560 this. The issue here is how you starve the fermentable fuels without causing-

01:13:23.140 Without starving the normal cell.

01:13:24.360 Yeah. And, or harming at all. It sounds to me like you were brutalized in that experiment.

01:13:28.400 Well, yeah, yeah. That's a not to be done at home.

01:13:31.100 That's not what our goal is here. Our goal is to emerge from the therapy healthier than when you

01:13:35.380 start it. So the question becomes, how low can you get blood sugar without compromising

01:13:40.200 the health status of the individual? And again, if you're in ketosis, you can push your blood sugars

01:13:46.360 down really low.

01:13:47.620 But you'd want to do this without insulin because insulin itself is pro-tumorogenic.

01:13:52.180 Only if the blood sugars are high enough. Once you get those blood sugars down and you take away all

01:13:56.740 the glucose from the body or the majority of it, it kills the tumor cells. We have the data to

01:14:01.060 support that.

01:14:01.560 Insulin per se is killing the tumor cell or the reduction of glucose?

01:14:05.840 The reduction of glucose.

01:14:07.260 Even, so you're saying basically-

01:14:08.820 Because you can't eat insulin.

01:14:10.040 Insulin doesn't give you ATP.

01:14:11.860 So, but you're saying insulin does not function as a growth signal outside of its anabolic activity

01:14:19.180 and taking up glucose?

01:14:20.320 Well, if you have high, like insulin, like growth factor, of course, is linked to the insulin,

01:14:24.360 of course, that facilitates the uptake of glucose. I mean, if you don't have glucose,

01:14:28.040 if you don't have glucose, what doesn't make any difference? What else is going on? Because

01:14:31.500 without ATP, you can't get energy anyway. So, the goal is to take, deplete the sources of fuel

01:14:37.220 to the cells. So, insulin, you can't eat insulin. Now, insulin drives the pyruvate dehydrogenase

01:14:42.780 complex, which facilitates, that's why they say, oh, you know, you can get this and that.

01:14:46.900 That's only if you have a lot of glucose around. Insulin becomes pro-tumorogenic.

01:14:50.960 But if you have very little glucose and you give more insulin, remove the, it doesn't stimulate

01:14:54.640 tumor growth. We have direct evidence to support that. So, in fact, the Germans used to do that. 0.98

01:14:59.640 They used to put people into insulin comas. The problem is you don't want anybody going to an

01:15:03.880 insulin coma. If they were in ketosis, you could give a shitload of insulin and you're not going

01:15:07.880 to die. We have evidence in the literature to support that. So, you got to keep the door shut

01:15:13.540 on that insulin or on the glucose as tight as you can without harming the rest of the body.

01:15:18.940 So, we use insulin and then we do hyperbaric chambers, but that comes only after you shut the door

01:15:24.040 on the insulin and the glutamine. So, if you-

01:15:26.460 So, how do you shut the door on glutamine?

01:15:27.600 The glutamine door, you have to use drugs. And the best drug we've found so far is

01:15:31.040 don6-diasin, norleucine. It's an old drug, was made years ago. They used to use it on cancer

01:15:38.760 patients, but they never targeted glucose at the same time. So, the tumor cells were sucking

01:15:43.120 down the glucose. As a matter of fact, you can even make the more glucose sensitive if you take

01:15:47.580 away the glutamine.

01:15:48.020 So, there's no dietary strategy that could effectively reduce glutamine?

01:15:51.480 No. Glutamine is a non-essential amino acid. We can make glutamine from glucose. I mean,

01:15:57.100 so, it's why it's called non-essential. However, in physiology terms, it is essential. It plays a

01:16:02.200 massive role in the gut, in the immune system, in the urea cycle. I mean, it's such an important

01:16:08.140 amino acid and it's ubiquitous. It's the most abundant amino acid in our body.

01:16:11.980 Yeah. That's a funny distinction. I'm glad you pointed that out for this is a total aside,

01:16:16.040 but I'm sure that there are people listening to this who get confused by the term essential and

01:16:19.620 non-essential because it's eight of them are essential and 12 are non-essential or something

01:16:22.820 to that effect. But what you're pointing out is an important distinction. They're non-essential

01:16:27.340 because we don't have to get them exogenously. They're still essential for our survival once

01:16:33.320 produced endogenously.

01:16:34.860 Yes, absolutely. And glutamine, if you look, it's the most abundant amino acid in our serum. It's

01:16:39.740 everywhere. And our immune system-

01:16:41.380 So, the point being, there's nothing you're going to eat or not eat that's going to change that.

01:16:44.440 People ask me that all the time. It's got to be drug. You got to do it drugged. And you have to

01:16:48.480 use drugs, but it has to be done strategically. And you have to have people that are knowledgeable

01:16:52.360 about this. You can't just have some guy just jack you up with a drug that blocks glutamine

01:16:56.440 because it has to be because your immune systems will be compromised. And our immune system is needed

01:17:02.400 for the health of our gut, the health of killing bacteria. And if you use, if you paralyze them too

01:17:07.520 much, then you're going to get infections. You're going to have all kinds of other issues.

01:17:10.640 So, that's why we developed the press pulse concept. So, you press the glucose hard with

01:17:16.560 diets and drugs, and then you pulse the glutamine. So, what we think is going to happen is we will

01:17:21.980 target the glutamine with a drug that will selectively kill tumor cells, paralyze the

01:17:26.900 immune system, but then immediately give large amounts of glutamine back. And the issue, of course,

01:17:32.140 is that you're going to restore your gut and you're going to restore your immune system because

01:17:35.280 they're only paralyzed. They're not killed.

01:17:36.660 And when you say immune system, are you referring to the cellular or humeral system?

01:17:41.900 The cellular, mostly the cellular.

01:17:42.660 Because you've implicated, we're going to come back to it, but you've kind of implicated the

01:17:46.100 humeral system with the macrophage in terms of mutagenesis.

01:17:49.980 Well, we're talking about the cellular immune system.

01:17:53.560 Yeah, you're talking about the T cells.

01:17:54.700 And B cells and macrophages and natural killer cells, leukocytes, all these kinds of things.

01:18:00.460 They're all glutamine dependent. They're all heavily glutamine dependent. Okay. So, if you have a

01:18:04.740 patient that's burned the skin, now you're opened up to bacteria, you have to give large amounts of

01:18:10.000 glutamine because the immune system is needed to kill the bacteria. You have to restore the gut

01:18:15.440 function. A lot of the cells in the gut are glutamine dependent. So, that's why you give large

01:18:21.160 amounts of glutamine to cancer patients that have been subjected. But the problem is, of course,

01:18:26.260 is the tumor cells are using the same fuel. So, you have to know. And as I said, if you kill too

01:18:32.420 many of the tumor cells too quickly, you've got to have a cell system to remove the corpses.

01:18:37.020 You've got to have some, and that's what the macrophages do and some of these other immune

01:18:41.240 cells. They'll come in and remove the dead cells. Otherwise, you get infections. You die from the

01:18:45.700 indirect effects of these things. So, you have to know how to strategically target glutamine without

01:18:50.820 compromising the normal physiological systems that we have.

01:18:54.780 So, before we get into the therapeutic stuff, which I understand is probably what everybody wants

01:18:58.080 to hear about. I still want to get back to kind of understanding some of this stuff a little bit

01:19:01.400 better. So, experimentally, I'm still struggling with this sort of chasm in belief systems between

01:19:08.700 what sounds like the majority of people who take the view that says, look, the respiratory system of

01:19:14.840 the cancer cell is relatively normal. If you're seeing an increase in fermentation, it's an artifact of

01:19:21.460 a higher throughput of substrate to generate more building blocks. This strikes me as a very testable

01:19:26.340 hypothesis. This really shouldn't be, we shouldn't be debating this. There should be a set of

01:19:30.340 experiments that could resolve that, correct?

01:19:32.040 Well, yeah. And I think that diagram there on the board is the illustration of the strategy to

01:19:38.320 test that hypothesis, basically, which is where are they getting their energy from? The bottom line is

01:19:43.280 where are they getting their energy from? If you stop their energy-

01:19:45.740 The board picture, by the way, we're looking at everything. We're looking at the, we'll put a picture

01:19:49.520 of this, of course, up there, but it's basically the TCA along with everything outside of the TCA as

01:19:55.400 well. It's effectively looking like, it's even metabolic pathways that I can't name at this

01:20:00.080 moment.

01:20:00.340 Yeah. It's because you have to try to integrate, like you said, you have to try to integrate all

01:20:04.400 of the knowledge that we have on the biochemical systems into a strategy to manage the disease.

01:20:09.020 And I break it down into more simplistic things. In other words, energy. Without energy, nothing

01:20:14.740 grows. And the evidence that I'm convinced about, that I've read massive amounts of literature and

01:20:21.000 looked carefully at everything, the structure and function of the mitochondria in tumor cells

01:20:25.840 is compromised. All right. That's a fact. That's, in my mind, that is a solid fact. And to deny that,

01:20:31.960 one would have to ignore the evidence that I've looked at. You have to look at a mitochondria and

01:20:37.340 say, no, that mitochondria that has no cristae and is very few in number, there's nothing wrong with it.

01:20:42.900 Okay. Let's call it white, black, and black, white. I mean-

01:20:46.560 But let's go one step further because there's an objective way to assess structure. But shouldn't

01:20:54.140 we just ask the functional question?

01:20:56.100 Well, as I said-

01:20:56.860 Experimentally, I mean.

01:20:57.660 Yeah, of course. And we do that. So we know structure dictates function. That's a common

01:21:03.400 in biology. Then if that structure looks abnormal at the electron microscopy level, at the various

01:21:08.880 levels, why don't we look now at the activity of the proteins in the electron transport chain?

01:21:14.440 And just as an, this may be a naive question, but there can be large ranges of structure that

01:21:21.300 could still produce optimal function. And you would think that for something as important as

01:21:26.100 respiration, which to your point might be the single most important function of a cell as

01:21:32.000 evidenced by the fact that toxins like cyanide are uniformly fatal within seconds, you'd think

01:21:37.320 that the structural leeway within a mitochondria would be so high that you could, let's just

01:21:44.520 say you could quantify structure as a scale from one to 10. And obviously a 10 out of 10

01:21:50.400 structure is perfectly functional. You'd want to believe that that thing would function good

01:21:55.440 enough down to like a two out of 10. And only if you were staggeringly compromised, does everything

01:22:00.880 go to hell? So in other words, just to push back for a moment, one could argue, hey, yeah, of course

01:22:06.040 there's structural changes, but they're not functionally relevant because they're within a

01:22:10.780 parameter space.

01:22:12.020 Yeah, no, that's an important point. And I think the normal flexibility of our cells-

01:22:16.100 Yeah, that's the better word. It's the flexibility.

01:22:17.780 Yeah, the normal flexibility is able to accommodate those kinds of changes over the short period of time.

01:22:23.300 Mitochondria is such an incredibly vibrant system. It's a living organelle inside of

01:22:28.760 our cells, right? It's a separate organism actually.

01:22:31.680 Separate DNA.

01:22:32.520 Yeah. And they've turned over all of their DNA to the nucleus except for 13 critical genes. And

01:22:39.720 those 13 critical genes control the life of the cell. And so why should I do this activity when I

01:22:47.260 can get a dumbass nucleus to do it for me? But I'm still going to hold the keys to the kingdom. 0.97

01:22:51.820 There's still 13 genes that if anything goes wrong with them, you're dead. And this is the

01:22:56.480 whole thing, why cancer cells don't die through the apoptotic mechanism. Because the very organelle

01:23:00.740 that controls the kill switch, the switch doesn't work. So the cell bypasses the normal control of

01:23:08.180 life apoptosis in the cell because the very organelle that dictates that is now defective.

01:23:14.460 So consequently, this cell now is reverting back to the way it existed before oxygen came into the

01:23:19.720 atmosphere on the planet. They were all fermenters. They grew with unbridled proliferation until the

01:23:25.220 fermentable fuel in the environment disappeared and they all died. So it was very clear what was

01:23:31.060 going on before oxygen came into the atmosphere. Cells would proliferate unbridled. Albert St.

01:23:36.780 Georgi, there's alpha period in the existence of the planet. So everything was working on substrate

01:23:41.000 level phosphorylation. It was no oxidative phosphorylation. They're all doing that.

01:23:44.740 What we have in our system today is these same capabilities, but we don't use them,

01:23:51.160 but only for very short periods of time under very various physiological stress situations.

01:23:57.020 They don't become permanent. In the cancer cell, they have become adapted because as Warburg said,

01:24:03.300 you can't get a cancer cell from a cell that cannot ferment. So neurons in the brain can't ferment for

01:24:08.500 very long. You rarely if ever get a tumor out of a neuron, except neuroblastoma, which is outside the

01:24:13.760 brain. So heart cardiac myocytes rarely form cancers. Even muscle cells rarely form because

01:24:19.240 you have the sheets and stuff. So cells that need a lot of oxidative phosphorylation rarely can form

01:24:24.320 a tumor. Only tumors can form in those cells that can upregulate fermentation pathways. If you can't

01:24:29.520 do that, you're going to die. But wait, wouldn't skeletal muscle be one of the highest candidates to

01:24:34.220 be able to upregulate fermentation given their ATP demand? Yes, but they have a syncytium of mitochondria

01:24:39.580 inside the muscles and they've adapted. This is their part of the normal physiology. They can

01:24:43.740 ferment for periods of time under extreme stressful conditions. They can't permanently do that. They

01:24:48.880 die. The muscles will die on you. The cells will die if you try to force them into a long-term

01:24:53.960 fermentation metabolism. But they have the capacity to upregulate fermentation for short periods of

01:25:00.420 time, like many cells do. But brain can't do that. Heart can. You're going to have a heart attack.

01:25:04.700 Let's go back to the, this is an interesting point you bring up. Let's go back to a myocyte

01:25:09.900 within my quadricep versus a epithelial cell in my colon. To your point, the probability I will

01:25:18.740 get a cancer that comes from the myocyte in my quadricep is virtually zero.

01:25:23.680 No, I didn't say virtually zero.

01:25:25.180 But it's, I mean, outside of a sarcoma.

01:25:27.640 Sarcoma is, well, you know, what is a sarcoma? What's the origin of the sarcoma? What kind of

01:25:31.560 cell? It depends. It can be a myoliosar coming. There can be many. But just humor me for a moment.

01:25:36.020 Probability-wise, the myocyte in my quadricep or my pecs or something forming cancer is so much lower

01:25:42.680 than the epithelial cell in my colon, right?

01:25:45.120 Yeah. Or an epithelial cell in your kidney or your bladder or one of these kinds of things.

01:25:49.000 I just pick colon because it's such a high cancer probability.

01:25:51.500 Right, sure. Breast is another one. 1.00

01:25:52.960 Yeah, yeah, right. So what is it, explain to me again the difference in their, because I would say

01:25:59.600 like the muscle cell is far more adaptable at making lactate when it needs to, because it's,

01:26:05.380 I demand of it much more than I demand of my colonic epithelial cell. But then say what you

01:26:09.620 were saying again about the toxicity of lactate to that cell versus the epithelial cell in my colon.

01:26:13.740 Well, the epithelial cell in your colon, if it becomes, and again, it's a longer process,

01:26:19.600 you know, it's not something, you don't go from a normal cell to a cancer cell overnight in a colon.

01:26:25.260 There are some situations where cancer can happen much quicker than people would normally think,

01:26:31.020 but in general, it's like it's a protracted process. So the cell has to have the capacity

01:26:36.780 to shift from an oxidative process to a fermentation process. You have to have the

01:26:43.620 machinery in the cell to be a fermenter, because without that capacity, you can never become a tumor

01:26:49.180 cell. Because the cancer is twofold process. One is the gradual chronic interruption in respiratory

01:26:57.140 function, coupled with a gradual compensatory shift to the alternative form of energy, which is

01:27:06.380 substrate level phosphorylation. So if the cell is incapable of making that shift, it will never

01:27:12.940 become a cancer cell. It can't, because in order to be a cancer cell, you have to be able to replace

01:27:18.140 oxphos with fermentation. And if you can't do that, you're not going to become a cancer cell.

01:27:23.320 And that's why brain neurons rarely become tumor cells, because they can't do that. Brain cells die.

01:27:29.500 So if you interrupt oxidative phosphorylation in the neurons of our brain, we call that

01:27:34.800 neurodegeneration. So we don't generally get tumors. We get tumors from the glial cells and the

01:27:39.740 microglia and these kinds of things.

01:27:41.300 Yeah, this isn't important. I mean, I know what you're saying, but I know the listener will be

01:27:44.300 confused by this because they're going to say, but gosh, my aunt had brain cancer. 0.89

01:27:47.480 It's very important that we distinguish between the glial cells and the neurons.

01:27:51.480 And the microglia, there's another form of which we think are neoplastic.

01:27:54.300 But when we hear about astrocytomas, which would be the most common brain tumors,

01:27:58.520 they're not actually, the cancer is not existing in the neuron.

01:28:02.500 That's correct. They're not neurons. So these are the kinds, or cardiomyocytes.

01:28:06.500 You generally, because you're going to, you know, they just, they die. These, because you're

01:28:09.840 packed with mitochondria and you start, they start fermenting. You can't, they die. They can't deal with

01:28:14.480 that. Again, see, that's the part, Tom, that just confuses me. It's so counterintuitive.

01:28:18.300 I would think that if there's going to be a cell in my body that I want to be able to buffer lactate

01:28:24.000 and specifically buffer the hydrogen ion that comes with it, that's actually what's killing the cell.

01:28:28.800 I would want my cardiac myocyte to be the single most robust cell in the body because it has to be

01:28:34.240 the last guy standing.

01:28:35.520 Yeah. Well, you know, this is the whole thing. When you get a, when you get a heart attack,

01:28:38.660 you die from brain damage. You don't die from, your liver and kidneys are fine. That's why you can

01:28:42.400 donate your liver and kidneys when you have a heart attack because those cells are not dying

01:28:45.980 because they have the, they have the brain is most susceptible to the hypoxia. But the point is,

01:28:49.740 even at the level of the highest stress, I would want my cardiac myocytes to be able to access all

01:28:56.880 fuels, glucose, fatty acid, ketone, you name it.

01:29:00.440 They do that with heart, degenerative heart disease, but they don't form cancer. They have a

01:29:05.520 capacity. And this is where we found a lot of substrate level phosphorylation in the mitochondria,

01:29:10.380 the TCA cycle was discovered in stressed hearts. Okay. So, because they were saying,

01:29:16.340 well, the heart should be dead, right? I mean, why is it still functioning here? Where's the ATP

01:29:20.140 coming from? And they found that the way most of the energy in the heart is coming from mitochondrial

01:29:24.700 substrate level for shorter periods of time. I'm not saying this is a, you can't do this as a

01:29:28.720 permanent shift, but the concepts were developed from the word, the work in the heart, but you would

01:29:33.580 expect. Yeah. Well, same with my brain. I mean, why that, I mean, if your brain damage,

01:29:37.740 you can't function either. I mean, so the two organs, heart and brain are remarkably dependent

01:29:44.860 on oxidative phosphorylation for function and disruptions of oxidative phosphorylation are

01:29:50.020 usually catastrophic for those cells. I mean, of course, after time. I think I understand your

01:29:54.480 argument. What's your, I was thinking about it in reverse. You're saying because the brain and the

01:29:59.000 cardiac myocyte have evolved to be so efficient under oxidative conditions, it's not so much that

01:30:05.620 lactate is harmful to them. It's that once you start to disrupt, if the hypothesis is correct,

01:30:12.560 that it's the disruption in the mitochondria and its capacity to carry out oxfos that's harmful,

01:30:19.960 you die long before you get bother getting cancer. Those cells get, undergo apoptosis or just die.

01:30:25.660 I understand your point.

01:30:26.780 Yes. That's the point. That's the point. So, so the key is that how long does it take to

01:30:31.300 transition a cell from an oxidative phosphorylated state in a cell that can become a tumor like a

01:30:35.820 colon, as you mentioned?

01:30:36.580 So the real problem that these other cells have where cancer is so ubiquitous, whether it be breast

01:30:41.020 or colon, according to this hypothesis, would be their metabolic flexibility. It's their capacity to

01:30:46.920 easily wax and wane between, I shouldn't say that. It's not their flexibility. It's their lack

01:30:53.160 of dependency on oxidative phosphorylation.

01:30:55.100 Well, they depend. I mean, obviously, like you said, with cyanide, I mean, it shuts down. Everything's

01:30:59.680 dead real quick.

01:31:00.440 But that happens so quickly that they don't have the ebb and flow.

01:31:03.180 It's their capacity to upregulate fermentation over time because it doesn't happen overnight. It's a

01:31:10.580 very gradual thing. And heart cardiomyocytes and neurons of the brain can't do that, that these

01:31:16.580 other cells are capable of doing. And as I said, what happens is the, again, you had that

01:31:21.920 mitochondrial stress response. And this is where your oncogenes come in now because the

01:31:27.400 oncogenes are transcription factors that upregulate fermentation pathways. So basically, when you

01:31:34.100 damage the respiratory system of a cell, HIF-1-alpha becomes stabilized. And now you can upregulate

01:31:42.360 glucose transporters into the cell. Myc is a glutamine. They all overlap each other. Lactic acid,

01:31:48.700 the dehydrogenase, you know, all these enzymes that are geared for maintaining a fermentation

01:31:53.900 metabolism, the transcription factors that make those pathways upregulated are the oncogenes,

01:32:00.140 basically. So the oncogenes have to facilitate. If you're not going to get the same level of energy

01:32:05.940 out of your oxfos, you've got to compensate to get, because as I tell everybody, the singular most

01:32:12.120 largest consumer of energy in any cell is the pumps. These pumps that are on the surface of

01:32:18.640 the cells that maintain the ionic gradients that allow what we call life. Because once you reach

01:32:24.340 equilibrium, you're dead. So most of the energy in any cell, cancer cell, heart cell, and it's the

01:32:30.600 proton motive gradient across the membrane that determines whether or not that cell is going to be

01:32:35.760 alive or not. So you need ATP for that. If the ATP dissipates, you swell and die. You undergo apoptosis

01:32:42.880 or whatever. So you have to then determine, you know, where's my ATP coming from? How am I going to

01:32:48.040 keep those pumps going? And if fermentation becomes a replacement, therefore I'm going to need a lot of

01:32:54.280 extra fermentable fuels to make up the loss of the energy that I'm getting out of oxfos.

01:33:00.480 So oncogenes have to turn on because they are the transcription factors that upregulate the

01:33:05.320 transporters for glucose and glutamine. So you're bringing in two alternative fuels to make up the

01:33:11.080 difference. And therefore the genetic behavior of the cell begins to change. And then because the cell

01:33:17.080 is now using damaged respiration, you throw out a lot of reactive oxygen species from the damaged

01:33:22.860 respiratory system. And they cause, they're mutagenic and carcinogenic. So the nuclear genome

01:33:28.780 gradually collects all these different mutations and defects coming from the ROS of the mitochondria.

01:33:34.040 But at the same time, the cell is not dying from this ROS because it's being protected

01:33:38.840 by the fermentation pathways of glucose and glutamine.

01:33:41.860 How much of that lactate is leaving the cell and going back to the liver to undergo the Cori cycle?

01:33:46.580 Yes, a lot of it. A lot of it does.

01:33:48.280 Has anyone ever looked at patients who have a very, very high tumor burden and seen if they

01:33:53.120 appreciably have higher serum lactate levels?

01:33:55.280 Yes. Blood cancers have been. In fact, there have been some patients who have had various

01:34:00.460 leukemias where they died of lactic acidosis from so much lactic acid being produced from

01:34:05.240 the tumor cells. There's a couple of papers reported on that. Lactic acidosis from massive

01:34:10.300 leukemias. Okay. So the leukemia, the same thing. It's a blood cell. They're mitochondria

01:34:15.360 defective. So they're thrown out a lot of lactic acid.

01:34:17.000 Although that's a confusing one because I could come up with another explanation, which is

01:34:20.820 in very, very severe leukemias, you could also create multiple end organ ischemia just due to

01:34:28.060 the defective nature of the white blood cells could actually cause capillary damage. And that

01:34:34.100 lactic acidosis could actually be from other organs.

01:34:36.420 That's true. And the paper that I read seemed to focus on the lactic acidosis from the cancer

01:34:41.320 cells themselves. But it doesn't rule out what you just said.

01:34:44.100 Yeah. And I don't know how you'd quantify the distinction.

01:34:46.020 No, it's another one of these things. But the question is, but you're right. You can't

01:34:50.360 like a solid tumor seeing a lot of lactic acid in the bloodstream. The Cori cycle clears it

01:34:58.160 out pretty quick. So you're going to be taking that lactic acid and making glucose again from

01:35:02.760 it, which then goes back to the tumor cells upregulate the machinery. I believe MCT2 is

01:35:08.220 the lactate transporter. Do they upregulate that specifically?

01:35:12.020 Yeah. I mean, it's upregulated and so is lactic acid, LDHA, lactic acid dehydrogenase A, which

01:35:20.120 converts pyruvate to lactic acid rather than B. See, most cancer cells do not have elevated

01:35:26.040 levels. This is why some people say, oh, cancer cells can burn lactic acid. Oh, where are they

01:35:30.900 burning it? Oh, well, because they're taking it back in. The cancer cells are burned. No,

01:35:34.540 that's bullshit. If it can't put pyruvate into the mitochondrids pumping lactic acid, how is it 0.99

01:35:39.560 possible? We're going to take lactic acid and make it back to pyruvate and put it in there.

01:35:42.540 If it does that, and it's going to go up to, you're going to store it as glycogen. It's not

01:35:47.160 going to be respired. But do you know if anybody's looked at that and seen if MCT2, I think it's MCT2

01:35:51.780 is the transporter. It should be upregulated a lot. Yeah, they're upregulated. There's no question

01:35:56.720 they're upregulated. Because otherwise the hydrogen ion would poison the cell. Yeah. So you have the

01:36:00.920 whole thing is upregulated, monocarboxylic acid transporters. They dump out, and they also take in

01:36:06.180 ketones. Don't forget, that same transporter brings in ketones. So when you go into ketogenic diets,

01:36:11.540 the MCTs are upregulated as well. So you're bringing in more ketone bodies now to replace

01:36:17.040 those. There's an irony for you, right? The thing that you use to bring in ketones is giving you

01:36:22.100 the exit for lactate, which protects the cell from the harm of the acidosis that comes with the

01:36:27.960 hydrogen ion. In the microenvironment of the tumor, it's a real mess. So some of the lactic acid is

01:36:34.160 persisting. The hydrogen ions are persisting until they can ooze out into the local bloodstream and

01:36:39.440 get back to the liver that way. But otherwise it's going to be a real acidic mess, which then

01:36:44.300 contributes further to the fermentation behavior of the cells, which then they're resistant. So

01:36:50.080 they're fermenting, right? So they don't need blood vessels. So this is the whole why the

01:36:56.660 anti-angiogenic field has failed. Because they said, well, we'll target the blood vessels and therefore

01:37:02.340 the cells will die because they can't get the oxygen and whatever. But the cancer cell doesn't

01:37:06.360 need that. I mean, it doesn't need the blood vessels. It can ferment.

01:37:09.500 Did you know Judah Falkman, by the way? You guys were basically neighbors here.

01:37:12.700 Yeah, yeah. I know he came down here, gave a talk. He targeted some unusual kinds of cancers with his

01:37:18.980 anti-angiogenic. But Napoleon Farrar, I believe, was the guy who started taking that all off. And he

01:37:24.160 even came to a meeting and said, none of this stuff is working. Well, because the... And this is why

01:37:28.380 Avastin, as I wrote, avoid it like the plague. It's a stupid drug. It was taken off the market 1.00

01:37:33.880 for breast cancer because it was harming more people than it was helping. But they still use

01:37:38.020 it for brain cancer. And I think it makes people...

01:37:40.260 They still use it? Do they still use it for colon cancer as well?

01:37:42.420 I don't know of colon cancer, but certainly for brain cancer. So what are you doing? You're

01:37:46.960 targeting the blood vessels and then forcing these cells to spread throughout your whole brain.

01:37:50.660 So just for the listener, right, Avastin is an anti-angiogenic drug. This was a genentech

01:37:54.920 blockbuster, right?

01:37:55.760 But Bevacizumab is the name of the drug. Yeah. And they still use it. I think it's despicable

01:38:00.180 to consider anybody using it. I mean, don't they know the biology of the problem? They would never

01:38:03.980 do that. And it's already been a bust in all the brain cancer studies that I've seen. In fact,

01:38:08.600 my friends have told me that work on this. But it makes the aim...

01:38:12.160 Well, it's generally been priced out of use. Certainly outside of the US, I don't think

01:38:16.320 any third-party payers would cover it. And it's a very expensive drug. It's about $100,000 a year drug.

01:38:21.460 Yeah. And all it does is contribute to the invasive behavior of your tumor cells.

01:38:24.520 And all of these other things, you're basically driving this idea, which I haven't wrapped my head

01:38:28.080 around yet, is you're actually enhancing the promotion of the hypoxic factors that are giving

01:38:35.080 cancer some of its selective benefit.

01:38:37.220 Yeah. And it's forced... And don't forget the cells that are invading, which are coming from

01:38:41.260 disrupted microglia in the brain, macrophages. They'll invade. They already have the capacity to

01:38:46.460 do this. They live without blood vessels. So you're facilitating the invasive behavior. And this

01:38:52.400 has been seen on histological preparations, like brains that have been looked at after

01:38:56.700 Avastin. They find tumor cells spread through everywhere in the brain. Rather than clustered

01:39:00.380 in one area, it's like they've just gone everywhere. But when you look at the image,

01:39:06.620 the radiographic images, it looks good because you don't see the necrotic area that you would

01:39:11.720 normally say, oh, it looks like it's like... The image looks a little bit better. You tell the patient,

01:39:15.540 it looks like it's working. But the overall survival is no different. Sometimes it's even

01:39:20.340 less. So it's a false image of what's going on. You can't see the big central area. It looks like

01:39:26.060 it's very vague and diffuse. And you look at the panel, yeah, it looks like this thing is working.

01:39:30.860 Gives the guy false hope. Because the end result is look at the overall survival statistics and

01:39:36.480 they're abysmal.

01:39:37.600 So I want to go back to something you said a moment ago. You said macrophage, which reminded me of a point

01:39:41.640 you brought up earlier, which I guess I'm just not really familiar with, which was the idea that

01:39:45.560 the macrophage themselves may be responsible for actual metastatic behavior.

01:39:52.780 Yes.

01:39:53.100 Can you say a bit more about that?

01:39:54.280 Well, this is a concept that goes all the way back to Akil from 1906 in Germany, where he was

01:39:59.920 able to show that in colon, I believe it was colon or melanoma, I can't remember the tissue. He was

01:40:05.940 actually observing fusion behavior between the neoplastic cells and the cells of our immune

01:40:11.820 system. And then claimed that he thinks after this fusion event, that these cells become much

01:40:17.820 more aggressive and much more dispersive than before these fusion events. This was then solidified by the

01:40:24.160 work of John Pawlik at Yale University, where he did some beautiful experiments showing that malignant

01:40:29.040 melanoma is actually a macrophage disease. They're resulting of fusion hybridization.

01:40:33.500 This was then further established by Melissa Wong and her group at the Portland Medical Center there,

01:40:39.480 the Health Science Center in Portland, Oregon. Beautiful work showing how in the colon,

01:40:45.500 how macrophages were fusing with neoplastic stem cells forming these hybrid cells.

01:40:51.820 So the question, and we know that all these metastatic cancers are highly fermentative,

01:40:56.380 all right? We know that's a fact. They're all highly fermentative. And they're all very,

01:41:00.880 very invasive and they spread. They migrate through the blood brain. They migrate everywhere. They just

01:41:06.320 invade. And these are all behaviors of macrophages. When you say fusion, so you have a neoplastic cell

01:41:13.700 that is above the basement membrane and you have a macrophage. And tell me what the fusion actually

01:41:21.460 is. Are they fusing genetic material or are they just fusing cytoplasmic material? What's actually

01:41:26.740 happening? Well, it's a combination of both actually. So macrophages, the cells of our immune system are

01:41:31.840 extremely fusogenic. Okay. They do this to wound healing. Like you'll see multinucleated giant cells

01:41:38.080 in a lot of parts of our bodies during wound healing and this kind of thing. And cancer cells,

01:41:42.620 you also find a lot of these multinucleated kinds of cells. So our body recognizes wounding

01:41:48.360 as an acute problem and the immune system will come into that local area to facilitate wound healing.

01:41:54.300 And when the wound persists, sometimes these cells will fuse with each other and fuse with other

01:41:59.440 cells in the microenvironment to facilitate wound healing. The problem is, is if you have an epithelial

01:42:04.880 cell like a breast cell or a colon cell that is coming and becoming neoplastic, becoming dysmorphic in

01:42:11.540 its growth regulatory and it's fermenting, but it doesn't have the capacity to grow anywhere outside of

01:42:17.520 that local area. It doesn't have, have the capacity. So our immune cells come into this

01:42:23.340 lesion, if you will, that's persisting. The immune cell throws out growth factors and cytokines to

01:42:29.080 facilitate the wound, to facilitate wound healing. The problem is those factors are also facilitating

01:42:34.680 the growth of the neoplastic cell. So the neoplastic cell is dysregulated, but the very cell that's coming

01:42:40.340 in to try to correct the wound is now provoking the cell to grow even more.

01:42:44.380 But what is the wound that the macrophage is coming in to see? Because the neoplastic cell has not yet

01:42:49.780 violated the membrane beneath it.

01:42:51.900 No, but it creates a, it throws out lactic acid and creates a kind of a hypoxic micro area. Okay.

01:42:58.420 A micro area of hypoxic, because the lactic acid is a signal of hypoxia. It's a signal of some sort of

01:43:04.440 damage. And you're not supposed to have pockets of build up lactic acid in parts of your body.

01:43:09.600 So it sends out, and normally if this does happen, if we have a contusion or a cut,

01:43:15.200 cells of our, the monocytes mass migrate out of the bloodstream, go into the wound,

01:43:20.160 clear up the debris, kill the bacteria, and then move out of that, out of that section,

01:43:25.160 go back to local lymph nodes and sit there in the event that they need it again. Or if they're

01:43:29.100 pus, they form pus. They're all massive numbers of white dead blood cells. So these cells are part

01:43:33.820 and parcel of the correction of the wound. The problem is in the, if you have a colon lesion

01:43:38.780 or a breast lesion from an occluded milk duct or whatever, or a lesion in the colon, you have

01:43:43.460 population of cells that will start to proliferate, creating a damage to the local micro environment,

01:43:48.440 signaling a system that's immune. There's something going on here.

01:43:52.180 Right. So when the monocyte gets out and differentiates, become the macrophage, goes to this

01:43:56.780 now poorly differentiated cell. Why doesn't it just kill that cell non-specifically? Because

01:44:04.080 this is just a macrophage. And how does that-

01:44:06.420 Well, macrophages aren't designed to kill cells. They're designed to kill bacteria that may be in

01:44:10.280 the micro environment. Don't forget they're a wound healing cell.

01:44:12.620 But going back to the bruise example, right? So you get a contusion in your thigh.

01:44:17.080 The macrophage does play a role in clearing that cellular debris.

01:44:21.120 Yes. Yes.

01:44:21.760 So why doesn't it just effectively do the same thing with the cancer cell or with the soon to be

01:44:25.580 cancer cell?

01:44:26.080 Yeah. Because the cell is not recognized as being, it looks like it's a part of the local

01:44:30.140 normal epithelial cells. Okay. It's not looking at it as if this is a foreign invader. This cell

01:44:36.940 has all of the, it looks like a regular epithelial cell that's proliferating. Because don't forget,

01:44:41.640 we replace our cells by proliferation.

01:44:44.280 But the lactate secretion, which is what got it there in the first place, wouldn't that tell the

01:44:48.860 macrophage, hey, something's still wrong here?

01:44:51.260 Yes. This cell is hardwired to do what it's supposed to do. It's not like thinking,

01:44:55.580 oh, let me problem solve. It's not a problem solving cell. It's hardwired to respond to a

01:45:01.620 particular environmental issue.

01:45:03.820 I see. So you're saying the lactate is the fire alarm that got it there, but then when it gets

01:45:08.440 there, it doesn't see the fire.

01:45:09.620 No. Well, it tries to put out the fire, but the problem is the molecules that are used to put out

01:45:14.880 the fire are actually stimulating the growth of the cell that shouldn't be grown. So it's out of

01:45:18.800 context.

01:45:19.240 Okay. So how does this facilitate metastases rather than just local advancement?

01:45:23.400 Right. So at what point in this protracted process does this now spring to become a

01:45:31.340 metastatic lesion over a controlled proliferative abnormality that's not yet breaking through the

01:45:39.420 basement membrane or doing this, right? So we don't know. Sometimes this can happen very fast.

01:45:46.000 Sometimes it takes a long period of time because we have these certain cancer cells called cancer

01:45:51.420 of unknown primary. They're highly metastatic, which is where the hell they came from, right?

01:45:54.720 We don't know what's, but they're very highly invasive. Then we have other cells that will,

01:45:59.940 well, he had a lesion there a long time for several years. This thing never healed. It was always oozing.

01:46:04.740 It was, and eventually explodes into a metastatic lesion. We don't know at what point,

01:46:09.700 and it varies from one person to the next. Now what happens is when the macrophages,

01:46:15.320 we know biology, they're fusogenic cells. There's massive amounts of biology to show that

01:46:19.900 macrophages are very fusogenic cells. They can fuse with themselves or with other fibroblasts. They can

01:46:24.820 fuse with a variety of different cells. Usually that's part of the wound healing process to facilitate

01:46:29.340 wound healing. But if you fuse with a stem cell that has already defective respiratory systems,

01:46:36.400 you would then dilute the cytoplasm of the cell that you fused it with. And it fuses again and

01:46:42.520 again. It's a process that takes place. You eventually dilute the normal mitochondria in

01:46:47.280 the macrophage, and you replace it with the abnormal mitochondria from the cells that you're

01:46:51.460 fusing with, then leading to a cell with dysregulated growth properties. How many mutations would it take

01:47:00.700 to do that? We don't know because there are some metastatic cells that don't have any mutations,

01:47:04.140 if you can believe it. Deep sequencing. They haven't found any mutations in some of these cells.

01:47:09.160 So, but they're fermenting and they're spreading. They have their growth dysregulated. So-

01:47:14.300 But wait, how are they growth dysregulated without a mutation?

01:47:17.300 You have cells that are carcinogenic, that are tumorogenic, that have no mutations. Baker pointed

01:47:24.880 this out. It's like people can't believe this. On the other hand, we have skin cells loaded with

01:47:29.420 so-called driver mutations that never form a tumor. So, this linkage between the number of mutations

01:47:36.380 and the type of cancer is just, there's so many flaws in this. So, there are cancer cells that have

01:47:43.460 been looked at that have highly invasive metastatic, and they can't find the mutations in there. That's

01:47:50.600 not common, but it happens. So, it throws it. It's a violation to the whole concept.

01:47:55.560 In glioblastoma, there are some tumors that have been found that have none of the driver mutations,

01:48:01.380 none of the abnormalities that you would have expected that are found in others. So,

01:48:05.920 there's a break linkage between mutations. You don't need new mutations to cause a metastatic

01:48:11.220 lesion. That doesn't mean that a metastatic lesion has no mutations.

01:48:14.940 But maybe I'm asking a different question. Okay. So, two women have breast cancer. 0.97

01:48:20.640 Right. And for all intents and purposes, they have very similar patterns of mutations in their

01:48:28.320 breast cancer. And let's just say, make it easy and say that they're hormonally similar. They're

01:48:32.800 ER, PR positive, HER2 new negative breast cancers. Both women present as stage T2N1, right? So,

01:48:42.980 they've got whatever, a five centimeter tumor, if that's still a T2, I don't even remember. And

01:48:47.060 they've got, you know, two lymph nodes or one lymph node. They both have a resection.

01:48:51.140 10 years later, one of them is still disease-free. The other one has died from brain metastases,

01:48:57.880 which were presumably seeded before the primary tumor was resected 10 years earlier. It's not a

01:49:04.620 sloppy surgery where they didn't get part of the cancer. What I'm hearing you say is,

01:49:09.560 yeah, one of them could undergo metastases while the other one did not, even though their primary

01:49:14.940 tumors looked very similar. Is that a correct inference?

01:49:17.580 Yeah. I think that's correct. And what we find now with a number of papers is the needle biopsies

01:49:23.240 that are used to diagnose the tumors can create a wounded, even a more aggressive wounded situation

01:49:30.520 in the microenvironment of the tumor, leading to the phenomenon of inflammatory oncotaxis,

01:49:35.920 which facilitates the fusion. And in other words, by looking at the tumor with a needle biopsy to make

01:49:42.200 the diagnosis, you put that patient potentially at risk for causing a metastatic lesion. And then

01:49:47.140 when you look at the profile, you say, well, this doesn't look too bad. No, not here.

01:49:51.780 But wait, let's say we do that. We're going to immediately resect that tumor anyway. So how is

01:49:56.840 that, how quickly does this process take place? Because the wound is between the outside world and the

01:50:02.560 tumor, not between the tumor and the inside world necessarily, especially if that tumor is going to

01:50:07.660 come out within a few weeks, right? Yeah. We know from a number of studies that needle biopsies

01:50:16.460 can facilitate in some patients the invasion of cells into the local and spread. All right. We know

01:50:24.460 this. This has been reported in the literature for breast, for colon, for liver, for brain. The very

01:50:29.840 act of stabbing this growth can. Well, but, but yeah, no, I think what's. So then you can get the

01:50:37.020 cells out. Yeah, but I think what's known is that you can seed tumors along the tract of where you do

01:50:42.160 that. Yes, that I understand. But maybe I misunderstood. You're saying that a woman who

01:50:46.060 has a needle biopsy of her breast, who then goes on to get a lumpectomy, has that increased her risk of 1.00

01:50:51.940 brain metastases? Well, it wouldn't be brain metastases right away. It would have to, that brain

01:50:56.560 metastases, the secondary metastatic behavior has taken a while. There's other, it's not just the

01:51:01.960 brain. But how does a needle biopsy increase the risk of that? The needle biopsy creates a more

01:51:07.120 inflamed condition. That's why you call it an inflammatory oncotaxis. And now this was one of

01:51:11.700 the reasons why they get rid of the morcellation procedure, because this is what was happening.

01:51:16.060 So these women were dying from metastatic cancer from morcellation. It's kind of a machine that used to be

01:51:21.540 made by Johnson & Johnson for removing uterine polyps. Well, you're taking a polyp and you're

01:51:27.880 grinding it up and creating inflammatory oncotaxis. Now, there might've been one polyp out of a

01:51:33.980 thousand that would have this. Right, but that's very different from the, I'm asking a very specific

01:51:38.100 question because here's my fear. What I don't want is anybody listening to this who's got a breast 0.99

01:51:43.760 lesion who thinks now they can't have it biopsied. I'm still, I think that's a very different case than

01:51:48.180 the example. Well, the evidence is clear in some cases, not all cases, not everybody who goes under

01:51:53.560 a needle biopsy is going to have metastatic cancer. No, but that's not the question. I mean,

01:51:56.940 what I'm asking is, is a woman, if you take a thousand women, you take, it's a thought experiment. 1.00

01:52:03.820 You take a million women with an identical breast cancer and you take half a million of them and you 0.99

01:52:11.480 just do the resection and the other half a million, you do a needle biopsy to confirm the diagnosis.

01:52:17.240 Then you do a resection. Are you saying in the half a million women that had a resection following

01:52:23.940 a biopsy, their probability of metastatic cancer later on is greater? I think so, but I can't be

01:52:30.540 sure because that experiment hasn't been done. Okay. I'm basing it on what has already been known

01:52:34.800 about needle biopsies facilitating the spread of the tumor. But I, again, I'm just being critical of

01:52:40.160 this because I feel very strongly about not causing panic in people, but I think those data are about

01:52:46.560 needle track seeding. Yeah. Well, needle track seeding. For example, like, as you said, you have

01:52:50.160 a liver biopsy, you can, you can get cancerous cells through the tract even after the, but that's

01:52:55.460 very different from saying, you know, cause that, that can be dealt with, but this is a very different.

01:53:00.540 Yeah. Well, I think this is from what I'm looking at. Now I look at the brain predominantly,

01:53:04.380 right? You know how many we have, what we call secondary glioblastoma. And that is a very,

01:53:10.300 it's not uncommon that when you go in and remove a low grade tumor that within a shorter period of time,

01:53:15.700 it turns into a glioblastoma. This is the same phenomenon. You're just doing it on a little bit

01:53:20.760 larger scale rather than just through a needle biopsy. So you go in and you take out a low grade

01:53:25.220 tumor and all of a sudden within a year or something, you've got glioblastoma, sometimes even

01:53:29.520 less. And you're saying, what the hell happened here? So this is just a larger, what's the control

01:53:34.180 for that observation? Well, there meaning like another explanation would be the person who has the

01:53:39.560 stage one astrocytoma is more at risk for the stage two, three, or four astrocytoma.

01:53:45.260 From the operation itself, from the provocation of the micro environment.

01:53:49.180 But without it, we'd have to have a group of those patients who don't undergo surgery.

01:53:52.160 That's right. And you would have to, but who's doing, nobody's doing these experiments,

01:53:56.040 but we, but here, here's the situation. What our philosophy is that is if we shrink the tumor,

01:54:02.360 whether it's a breast tumor, colon tumor, or whatever, if we take away the fermentable fuels

01:54:07.280 and shrink that tumor down, then it becomes a candidate for complete debulking, not, not

01:54:13.260 diagnosing. Okay. When you take a needle biopsy of a breast and you look at what are they,

01:54:20.660 why are they doing that? They're doing it for majorly two reasons to try to diagnose what level

01:54:24.360 of cancer you have. And then to give you a gene readout, like these genes are going to play some

01:54:28.960 role in whether or not you're going to get a treatment, right?

01:54:31.280 Well, yeah. But it's, for example, in the case of doing a biopsy before a breast resection,

01:54:37.780 you, there's value in knowing if a woman might benefit from neoadjuvant therapy, for example,

01:54:42.360 based on their receptor profile. Yeah, but in other words, it might not just be the gene,

01:54:46.480 right? Like knowing that she's ER, knowing that she's triple positive versus triple negative might

01:54:51.260 change what you do. Yeah, I guess it could. But, but the bottom line is, is that why don't you

01:54:55.800 assume that you have a problem? Why don't you just put that patient on metabolic therapy?

01:55:01.280 And shrink that tumor down and then do a non-invasive check. Did it, did the borders

01:55:07.760 change at all from the, from the metabolic and then just the bulk it completely? The probability

01:55:13.260 of cure is going to be better in my mind than if you do a needle biopsy without doing the debulking.

01:55:21.260 And just to say, let's look at this. How long after the needle biopsy do you put that patient at risk

01:55:26.860 for possibly seeding a cell that gets into a lymph node that then can spread out and later that you

01:55:33.340 get brain metastasis, liver metastasis or whatever else can happen from these cancers? So the question

01:55:39.020 is why put anybody at risk? If we know we have evidence from the literature to say that is a

01:55:44.880 possibility, why would we want to put anyone at risk for that? Unless the information you get from

01:55:51.860 the needle biopsy is going to be a curative procedure. And a lot of times it's not. Okay.

01:55:56.960 It's just for diagnosis procedures. And now today we're using all these gene screens, $7,200 to tell

01:56:02.900 somebody what kind of gene profile. And that may no longer be relevant after you've taken a needle

01:56:07.780 biopsy from the very tissue that you're doing. Yeah. No, I think that makes sense. I guess I'm

01:56:11.540 a bit confused by the idea. I guess I just don't see.

01:56:15.140 Those are controversial issues. And I'm looking at it from the point of the biological processes

01:56:20.400 that are taking place from these procedures. And knowing that I've seen literature on lung,

01:56:27.000 I've seen on liver cancer, certainly for brain.

01:56:29.340 I mean, but here's, so, I mean, there are so many potential arguments, right? So you look at one of

01:56:35.400 the most metastatic cancers of all time is pancreatic cancer, right? It's almost uniformly fatal. And yet up

01:56:43.580 until recently, very infrequently biopsied. It's a very difficult biopsy. You have to do it with an

01:56:49.360 ERCP. No, that's true. So yet, in other words, you can still have incredibly aggressive metabolic

01:56:54.720 cancers, which have never, which are, you know, are not biopsied often. And then conversely,

01:57:00.000 you look at a GBM, you look at a, you know, the cancer we're sitting here talking about the brain,

01:57:04.680 you know, a very aggressive, the one that John McCain just passed away from. Well, that's,

01:57:09.020 I mean, that's only locally metastatic. It never leaves the CNS, does it?

01:57:13.060 Oh, yeah, it does.

01:57:14.400 Where does it go?

01:57:15.120 It goes to bone. It goes to liver. It goes to, nobody looks at the-

01:57:18.700 What percentage of patients die from, or-

01:57:21.660 Not many, but when they look, they find. This was one of the big things. This is how we

01:57:26.420 discovered the macrophage origin of the cancer. We started looking and say, how many people do

01:57:31.960 autopsies of organs on people who've died from glioblastoma?

01:57:35.780 And what did you find?

01:57:36.800 There's a hundred articles in the literature with metastatic GBM to various organs for people dying.

01:57:42.100 People say, well, it doesn't happen that often. You know why? They die the GBM before they start

01:57:46.100 recognizing they have metastatic liver cancer. But when you look at livers and kidneys and these

01:57:50.600 other organs from patients who have died from GBM, those studies that have looked have found cancer.

01:57:56.040 So clearly, these cells are coming out of the brain, and they're getting into the other organs.

01:57:59.840 The problem is the patients aren't living long enough to have a problem. Well, who's worrying

01:58:03.280 about the guy's liver when his brain is starting to swell up from all the treatments they're giving him?

01:58:07.980 I mean, 12 months, most people are dead. But there's over 100 articles in the scientific

01:58:15.280 literature showing outside, I call it extracranial metastasis of glioblastoma.

01:58:21.360 So it's not that it's, and people ignore it. It's like knowing that the mitochondria damaged

01:58:26.220 in cancer cells, people ignore it.

01:58:28.380 Well, I guess that'd be a more forgivable thing to ignore because I'm not convinced it

01:58:32.980 necessarily changes the story. The mitochondrial one is a much more interesting question, right?

01:58:37.660 I mean, that to me, of all the things we've talked about today, Tom, that's the one that

01:58:41.180 kind of has me scratching my head the most and wondering, in 2018, how are we even having

01:58:47.880 that? This should be something that's not debated. This should be sort of like, this would be like

01:58:52.700 debating whether DNA is necessary to make RNA. That discussion was settled in the 50s, and anyone

01:59:01.120 who disputes that now is sort of disputing the shape of the earth.

01:59:04.680 So I guess, to me, given the stakes here, I would love to figure out why people aren't

01:59:10.340 answering this question.

01:59:11.240 Well, let's look at the situation from even a greater distance. In the United States, we have

01:59:17.160 over 1,600 people a day dying from cancer. I mean, this is horrific, right? There's over a half a

01:59:22.940 million people a year, 1,600 people a day dying from cancer. Obviously, there's something seriously

01:59:28.020 wrong. There's something massively wrong with what we're doing with this disease. You know,

01:59:32.800 we talk about needle biopsies. We're talking about this. We're talking about that. The issue is we

01:59:37.320 had 1,600 people a day dying. Why are all these people dying from cancer? So it's either we have

01:59:42.140 a fundamental misunderstanding of what the nature of the disease is. We're mistreating it. We're

01:59:46.920 treating it as something that other than what it actually is. So the debate that you mentioned now

01:59:52.240 is that the results of the dead people are the consequences of the fundamental misunderstanding

01:59:58.120 of the process of the biology of the disease. What I'm arguing is that now understanding the

02:00:04.420 biology of the disease, we have the potential to drop the death rate by more than 50% in 10 years.

02:00:10.240 There's no question about it. If you stop doing half of the stuff that we're doing to these cancer

02:00:14.360 patients, looking at the biology and the nature of the disease, how to best go about this strategically,

02:00:19.440 I think we can drop the death rate by 50%. We're doing stupid things, right? Needle biopsy tumor cells 0.99

02:00:25.640 for genetic profiling that has no relevance to the nature of the disease. That's just one.

02:00:30.780 But just to go back to that, because I'm sorry. I really want to make sure people aren't going to

02:00:35.160 stop refusing their biopsies. But have we seen an increase in the rate of metastases in the era of

02:00:41.560 needle biopsying for genetic sequencing? I mean, we could go back and look at the death rate from

02:00:45.740 cancer 50 years ago before anybody was doing this, and it was the same.

02:00:49.360 Yeah. Well, I think that we've probably... I don't want to say... I just want to say that every

02:00:54.220 year, we have more and more dead people. And the increase is faster than the general population,

02:00:59.480 okay? So we had 3.8% increase in death.

02:01:03.340 I don't know. Is that actually true? Is the age-adjusted, population-adjusted mortality

02:01:09.000 of cancer today higher than it was 50 years ago? I think it's about 3% or 4% lower, isn't it?

02:01:14.360 Well, I just did the last five years, okay, from 2013 to 2017.

02:01:18.680 But to test this hypothesis, we'd want to take an even longer time period and go more extreme as

02:01:23.920 far as like... Yeah. Well, I mean, every year, there's no year that we have fewer. They're

02:01:29.420 always coming. The dead people are piling up. So when I look at the numbers and I say, okay,

02:01:35.000 what was the percent of population increase in the United States over the last five years? And

02:01:40.260 according to the demographics, it's 2.9%. Okay. Over the same period, how many cancer deaths...

02:01:47.000 Right. But again, I don't know my epidemiology well enough to make this case, but I'm going to

02:01:51.160 try anyway. Isn't the growth in population more a function of the input of people, meaning birth rate,

02:01:57.720 rather than the people who are getting cancer, which are the older folks?

02:02:01.920 Well, we have younger people too, right?

02:02:03.720 Right. But the majority of cancers are older folks.

02:02:05.600 Yeah, majority of cancers are older folks, for sure.

02:02:06.700 So I'm not sure that that population argument would answer that question, right?

02:02:11.040 Well, maybe. There's always a guy you can find. I think all you have to look at is the numbers of

02:02:16.800 people that are dying from the disease. I mean, that's a fact. No, it's a fact, and it's a tragic

02:02:21.860 fact. I guess a 50% reduction in the mortality of this disease in 10 years is a very bold statement,

02:02:30.480 given that we've seen about a 3% reduction in cancer mortality in 50 years.

02:02:36.540 Yeah.

02:02:38.240 Which I think you're arguing is unacceptable and understandable.

02:02:41.320 Well, you know, yeah, I'm looking at it from the tragedy. In China, there's 8,100 people a day

02:02:47.240 dying from cancer. I mean, that's the number over there. Maybe that's the bigger population. But

02:02:51.140 the problem, it's now surpassed heart disease in their country. Clearly, it's not whatever we're

02:02:55.880 doing. And yes, 50%, if you did what we think you need to do and to manage this disease,

02:03:03.600 looking at it from the biology of the disease, you will, I think, I would not be shocked if we had

02:03:11.280 a 50% reduction in 10 years. So normally, I ask people what their dream experiment would be. But

02:03:17.760 I want to ask you two. I want to ask you this question twice. The first time I'll ask you this

02:03:23.920 question will be the easier one because it'll be the clinical trial. So what would be the dream

02:03:29.660 clinical trial to test the hypothesis that says we can reduce the mortality of cancer by 50%?

02:03:36.900 What would you want to put head to head to definitively ask that question?

02:03:41.020 Okay. So what we do right now is if we do metabolic therapy at all, okay, we do it at all. It's either

02:03:47.400 standard of care versus standard of care plus metabolic therapy. We're missing the critical control

02:03:53.800 group. Metabolic therapy without standard of care. What are we doing to these people?

02:03:58.860 So tell me what the experiment would be. Let's use breast cancer as an example. 0.95

02:04:02.380 Okay. Breast cancer. So you have your standard, whatever you're doing today. You got a lot of

02:04:05.500 people dying of breast cancer, metastatic breast cancer. So we're going to now take metabolic therapy

02:04:10.240 and we're going to combine it with standard of care, which is what the group in Turkey is.

02:04:15.840 And how is that? How would you integrate that? Let's talk about how you would do it,

02:04:19.080 not necessarily how it's being done. How would you, for the purpose of the experiment,

02:04:22.440 integrate standard of care with metabolic therapy?

02:04:23.440 Okay. So we would use the chemo and we would have people on, on metabolic therapy,

02:04:28.740 which would be lower. And you would do those in parallel?

02:04:31.200 You would have some patients that would be treated only with the standard of care,

02:04:35.360 which would, which would be our control. And then we would have people treated with the standard of

02:04:40.000 care plus reducing blood sugar, elevating ketones and targeting the energy metabolism, which we can do.

02:04:47.680 And would that include things like metformin or DCA or other things like that?

02:04:51.980 It could, it could include hyperbaric oxygen.

02:04:54.080 Yes. Yes. And that's what we're doing in Turkey. So it's basically standard. However,

02:04:58.140 in Turkey, we're doing the lowest dose of chemo that we can use to still be in compliance with the,

02:05:03.280 with the law. And if you get rid of now, the control, the...

02:05:07.200 And now your metabolic therapy alone group would be...

02:05:09.280 Metabolic therapy alone group.

02:05:10.040 What would that group?

02:05:10.860 That group would be the press pulse concept. So we down-regulate the glucose first,

02:05:15.680 shrink the tumor up, make the microenvironment less inflamed, less angry.

02:05:20.560 Then we...

02:05:21.240 Specifically tell me what would be in that. So you would put, these patients would be on

02:05:24.760 ketogenic diets?

02:05:25.600 First, we would lower their blood sugar gradually, depending on the status of the individual.

02:05:30.480 So you'd go into lowering their blood sugar, elevating their... Putting them to therapeutic

02:05:34.580 ketosis, essentially. So a lot of these people also have a multiple other series of metabolic

02:05:39.300 abnormalities. They have type 2 diabetes. They've got triglyceridemia. They have all kinds of other

02:05:44.260 things besides having cancer. So basically by bringing them into a state of therapeutic ketosis...

02:05:50.400 And how do you define that? Is that defined by the amount of glucose and ketone?

02:05:53.900 It's by the glucose ketone index that we published. We published the paper on this.

02:05:57.260 And what's the ratio that you...

02:05:58.600 It's a ratio about close to 1.0 or below, if we can get it. This is where the millimolar of ketone

02:06:05.040 and the millimolar of glucose are about the same.

02:06:07.080 And that people hit that somewhere between 3 and 4, I'm guessing?

02:06:10.260 Days after?

02:06:10.960 No. 3 to 4 millimolars tends to be the place where they're about the same.

02:06:14.580 It could be. It could be. It depends on the individual. Because some people have higher

02:06:18.980 glucose, higher ketones, and yet they still have the same ratio. So some people have very low glucose

02:06:24.120 and not that high of a ketone, but it gives them the same ratio. So the issue is get your ratio...

02:06:28.560 The only time I've been able to be at 1 to 1 is when I'm not eating anything.

02:06:32.700 Yeah. Well, it's variable from one person to the next. And then the other thing too,

02:06:36.400 we have to be very careful about, is a lot of cancer patients, very hard to get into 1. You're

02:06:40.800 a young, healthy guy. Guys that are young and healthy can get well below 1. Women are better 1.00

02:06:44.840 than men. We've done some studies. So basically... But cancer patients are freaked out because they

02:06:50.460 have anxiety. And anxiety elevates corticosteroids. And you have a tougher time bringing your...

02:06:55.900 So we also institute with the press, besides ketone supplementation, as Dom DiAgostino has

02:07:02.560 been telling, and the ketogenic diet. And then we have stress management, which includes music

02:07:08.200 therapy, yoga therapy. There's a variety of ways to reduce emotional stress. And that's a very

02:07:13.120 important part of the management. You have to let the patient know that their disease is not terminal,

02:07:18.760 that their lowering of the stress is going to make the medicine work.

02:07:23.240 So once we get the patient into metabolic ketosis, now we have options. Now we can start using insulin

02:07:29.800 therapy to bring the blood sugars down lower. We can put them into hyperbaric oxygen, which creates

02:07:34.300 oxidative stress predominantly in the tumor cell and not in the normal cells. The normal cells are

02:07:38.880 burning ketones that reduces oxidative stress.

02:07:41.440 When you say insulin therapies, do you mean actual insulin?

02:07:43.980 Yeah. We're testing that now. The Germans used to do that years ago, but we don't think we have to 0.98

02:07:48.400 put people into metabolic comas to do this. We think we can do it without it. We're testing it now.

02:07:52.980 So I'm working on it now. As we speak, we have these experiments going next door.

02:07:57.520 So the question is, you don't want to use insulin therapy unless you're in therapeutic ketosis. You

02:08:02.080 don't want to go into a hyperbaric chamber unless you're in therapeutic ketosis. And then we would

02:08:06.240 pulse with drugs that target glutamine. And together, you're removing the antioxidant capacity of the

02:08:11.700 tumor, making it vulnerable to hyperbaric oxygen.

02:08:14.040 How much can these drugs lower local levels of glutamine?

02:08:17.740 Enough to slaughter the tumor cells. 0.99

02:08:19.300 But what is, like, I don't know enough about this. Is that a 50% reduction that's necessary

02:08:22.860 to do that? Because you're getting about a 50% reduction in glucose based on the therapy

02:08:26.860 you've described.

02:08:27.280 We want to lower the glucose even further because you can do that. And with ketones,

02:08:32.440 correction, with targeting glutamine, it's got to be pulsed because you can't chronically reduce

02:08:36.580 glutamine to the availability, to the physiology.

02:08:39.360 But acutely, how much do you lower it?

02:08:40.900 We can lower it quite effectively. We can shut it. And well, don't forget, the cancer cell is

02:08:45.800 absolutely dependent on this fuel. The normal cells, they can burn the ketones also. So they're

02:08:50.420 not going to be energy deprived completely. Whereas the tumor cell will be deprived energy

02:08:55.320 completely.

02:08:55.780 Are there some cancer cells that preferentially utilize ketones?

02:08:59.260 No cancer cell can use ketones. You have to have a good mitochondria. And a cancer cell that

02:09:03.120 would have some oxidative capacity, a small amount of oxidative capacity, could burn some ketones.

02:09:09.660 But most of the most aggressive cancer cells can't burn ketones because they're mitochondria

02:09:14.360 defective, that you need a good mitochondria. That's why it's a selective. It selects for

02:09:19.520 enhancing the vitality of the normal cell while putting the cancer cell at a competitive

02:09:24.300 disadvantage. So the ketones are not to kill cancer cells. They're to provide the normal cells

02:09:29.460 with a fuel as an alternative to glucose, that the tumor cells can't use the ketones.

02:09:34.440 And there are many experiments like this. If you take cancer cells and grow them in a dish

02:09:38.860 without glucose and glutamine, just ketones, they die. But normal cells don't. The normal cells can

02:09:43.880 survive on the ketones without the glucose and glutamine. So it's very clear that the tumor

02:09:47.640 cells can't use it. And as I said, you have to have a good mitochondria to do this. So we're

02:09:52.040 selectively marginalizing these tumor cells because of their metabolic incapabilities.

02:09:56.420 But it has to be done strategically over time.

02:09:59.720 And where does the hyperbaric oxygen fit in? Is that part of the pulse, obviously?

02:10:02.880 Yeah, that's a pulse therapy.

02:10:04.040 And how much hyperbaric?

02:10:07.100 We want to try to replace radiation therapy with hyperbaric oxygen because the mechanisms of cell

02:10:11.860 death will be very similar.

02:10:12.600 So how many atmospheres?

02:10:13.780 We do it at two and a half atmospheres.

02:10:15.740 For how long?

02:10:16.480 Well, we were doing it for 90 minutes every day, something like this. So it's designed to put

02:10:23.600 oxidative stress, killing the tumor cells by oxidative stress, the same way a radiation

02:10:28.500 therapy would work. Radiation a lot of times doesn't work because the cells are in a hypoxic environment.

02:10:33.760 All right? So why are they in such a hypoxic environment? Because they're fermenting.

02:10:37.740 All right? They're blowing out all this fermentable fuels into the waste products.

02:10:41.920 Got to clean that all up. That microenvironment has to be brought back to a normal state.

02:10:47.080 And therapeutic ketosis, we published several papers showing that it's a powerful anti-inflammatory

02:10:54.620 therapy. It makes the microenvironment less inflamed. It's pro-apoptotic. It's anti-angiogenic.

02:11:00.180 So you're killing all these bad blood vessels and replacing them with normal blood vessels

02:11:03.960 that the normal cells will be able to use. So it's reconfiguring the microenvironment while

02:11:10.000 putting stress and killing tumor cells. Now the tumor becomes more and more vulnerable.

02:11:14.600 And now it becomes more and more damaged by drugs that are going to chip away at the surviving

02:11:19.700 cells. It's not something we're going to go in like a bull in a china shop. It's going to be a

02:11:24.080 gradual degrading of the tumor.

02:11:26.580 And where does the surgery take place here? Is the surgery taking place before all of this

02:11:30.720 happens?

02:11:31.180 No. The surgery would take place at some midpoint. Okay? The midpoint would be where the surgeon

02:11:36.300 now looks at the tumor and says, I can take care of this. It's not going to be a diffuse mass. It's

02:11:41.400 not going to be an angry inflamed thing where you have to cut out half the guy's colon in order to get

02:11:45.960 what you think is the part of the cancer that's it. No, this thing will be now much more shriveled.

02:11:50.900 We've seen it. It's much less angry. It's a micro, it's more demarcated. You can see it on this,

02:11:56.060 and the histological slides. You can see what the hell happened to this tumor. How come it's

02:12:00.840 smaller? How come it's more, the margins are more sharply defined? Because you took away

02:12:05.380 the inflammation that was being driven by the fermentation fuels. So you're shrinking this

02:12:10.760 tumor down. Now the surgeon comes in and can potentially cure these people that would be

02:12:16.520 maybe not curable in the past. So this is why I'm saying we can reduce the death rate by 50%

02:12:22.580 if you view the tumor as a metabolic problem rather than a genetic problem. The gene mutations

02:12:29.080 are all downstream epiphenomen. They're red herrings. Even Vogelstein, who still claims that

02:12:33.940 this is a bird Vogelstein from China, he still claims it's a genetic disease, but we're never

02:12:38.060 going to cure the disease by targeting the genes. There's too many mutations. It's all this kind of

02:12:41.880 stuff. But we can do that with metabolic therapy. We can actually eliminate the cancer based on

02:12:47.300 metabolic therapy. It's a process. Who's trained to do this? No one. I mean, we need physicians to

02:12:53.280 be trained to do this. They've been used to train to give high doses of radiation without killing the

02:12:58.780 patient or poisoning these poor people with drugs that are very toxic and keeping them alive so you 0.99

02:13:03.320 don't die from the treatments. This is absurd. Why are you using radiation and chemo in the first

02:13:08.860 place? Well, we have to stop proliferation. Okay, well, if they can't generate energy, they're going

02:13:13.440 to stop proliferating. They're going to die. What is the experiment, the clinical trial that

02:13:17.240 you're involved in in Turkey that you've alluded to? Yeah, so what we do, my colleagues in Turkey

02:13:21.660 do, is they use chemo, but they use the lowest possible dose. Is it for breast cancer? All cancers.

02:13:27.060 In fact, the results are the same. All cancers are the same disease. They're all fermenters. So once

02:13:31.020 you knew that they're all dependent on these two fuels, then all you have to do is target the two

02:13:35.560 fuels to put them at risk for elimination. The question is, how can you target the fuels without harming

02:13:40.960 the rest of the body? And that's the press pulse concept. So we know we can press things constantly

02:13:45.680 without harming the body, but we have to pulse the glutamine issue because we don't want to deprive

02:13:51.020 our normal immune system and gut systems of the very fuel needed to provide normal physiology in 0.85

02:13:56.020 those tissues. So this is why we have to pulse the glutamine issue. How many glutamine drugs are there?

02:14:01.520 Well, there's some coming all the time, but the one that works the best for us is Don.

02:14:05.780 Are there any that are in clinical trials in the United States?

02:14:08.140 Yeah. There's a couple. There's a few names of them. They target various aspects of the

02:14:13.420 glutaminolysis pathway. The problem is we have a drug that's called a dirty drug. It hits multiple

02:14:19.680 pathways of glutamine metabolism, and it seems to work better than all the other drugs, at least from

02:14:24.600 our perspective so far. Which drug is that?

02:14:26.760 This is Don, the 6-neuroleucine. It was used in clinical trials years ago, but it was partially

02:14:32.380 effective, but they weren't targeting. They weren't doing the full metabolic approach. If you don't do all

02:14:36.540 the parts of the problem, the horse is going to get out. It's still not going to be effective.

02:14:41.900 And today, no one anywhere on the planet is doing the kind of a therapy that we think need to do to

02:14:46.820 make this all work. Now, there's bits and pieces of it.

02:14:49.300 And then what are the drugs that are in current clinical trials that are targeting glutamine?

02:14:52.900 Well, there's a BEPTS, I believe, an acronym for another very complicated structure.

02:14:57.180 And then they're making Don analogs that are supposedly less toxic. What we find is with

02:15:02.520 the ketogenic diet, Don becomes far less toxic. So you can actually use far lower doses.

02:15:09.300 So I was talking to somebody the other day, is it better to wait for a pharmaceutical company to

02:15:14.160 build a new drug to target cancer, or is it better to develop a way in which a previously very effective

02:15:20.960 drug could be less toxic? And both of them, the end result is the same. You're going to get something

02:15:25.460 that's going to work far better than what was previously available. So how many clinics in

02:15:30.080 the country, in the world, are treating cancer as a metabolic disease using a strategy that will

02:15:36.260 take away the two prime fermentable fuels for the disorder? And the answer is no one. No one's doing

02:15:41.580 this. But this trial in Turkey is doing this? Well, they're not targeting the glutamine. So they're

02:15:47.100 doing these other processes. So it's the glucose, the ketones, the hyperbaric oxygen, but not pulsing with

02:15:54.720 glutamine, not the anti-glutamine. Not doing the glutamine. Nobody's doing the glutamine.

02:15:58.400 We tried doing that in our Egyptian patient that we published recently. We used chloroquine and we

02:16:03.140 used EGCG, which is a green tea extract. But they're not as powerful in the clinic. Now that poor

02:16:10.120 guy, he just passed away. We were devastated by this. We published the paper. He lived 30 months,

02:16:14.840 which is far longer than most people with a glioblastoma. He was doing really well

02:16:18.760 on metabolic therapy. We pushed off the standard of care for three months. So we did surgery after

02:16:25.020 three weeks of therapeutic ketosis, debulked the tumor, most of it, because you never get all GBM.

02:16:31.320 And then we were forced into the radiation therapy after three months, even though the guy was doing

02:16:37.340 remarkably well. So we said, why are we irradiating? Well, we have to, because it's part

02:16:41.600 of the standard. Even in, this was in Alexandria, Egypt. And then a year later, he starts developing,

02:16:47.460 or what, six or eight months later, he starts developing a headache. His head starts to swell.

02:16:53.820 And they did the compression, the bulking, and they found, looked at the tissue. There weren't

02:16:57.760 any tumor cells. It was dying from radiation necrosis that he took from the radiation.

02:17:02.200 So this is why I'm very much against it. I think we're not going to make any major advance in brain

02:17:06.540 cancer until we stop irradiating people with the brain, because you're creating a bigger problem.

02:17:10.540 And this is leading to the demise of all these poor patients. The survival after radiation is

02:17:15.840 almost zero. And that's, in my mind, it's becoming, it's doing in part to the radiation

02:17:22.060 that we're giving to these people. So whether they're dying from the tumor or radiation necrosis,

02:17:26.040 they're going to be dying. They shouldn't be doing that in the first place. So the standards of care

02:17:29.800 have to be dramatically changed in order to improve overall survival. So when I say we can drop death

02:17:37.080 rates by 50% in 10 years, we're not only dropping death rates, we're massively increasing overall

02:17:42.420 survival and quality of life at the same time. So I have a lot of anecdotal information with people

02:17:50.260 who have been treated with metabolic therapy, part of it. They're living far longer. Their quality of

02:17:55.080 life is much better. And when they die, they die in a very peaceful way. And some of my clinician

02:17:59.640 friends have been telling me this, these guys that are in these metabolic therapies. Their quality of

02:18:03.360 life is really good up until about two weeks before they die. Whereas the people do on standard

02:18:07.280 of care, never live as long. And their quality of life is horrific. They're living there. They're

02:18:11.640 incapacitated. So do you think that metabolic therapies offer the potential for cure or just

02:18:17.680 another therapeutic option? Because if you want to reduce the death rate by 50%, there's no lead time

02:18:24.760 bias slash therapeutic extension that's going to do that. That is a paradigm shift in cure, not treatment.

02:18:32.680 I think it's both. I think you're going to be able to extend dramatically overall survival. You're

02:18:37.880 going to improve dramatically quality of life. And how do we know if we're cured? The issue is that

02:18:44.900 if you die from a heart disease at 85 and you had cancer when you were 50, a so-called a terminal

02:18:51.360 disease.

02:18:51.820 No, I mean, I think we could pick something simpler than that, right? If you are 10 years disease-free,

02:18:57.600 to a first order approximation, you're cancer-free, right? If you had colon cancer 10 years ago,

02:19:02.660 and 10 years later, you die of a heart attack, I think it's safe to say you died of heart disease,

02:19:07.760 even if on an autopsy they find dormant cancer cells.

02:19:11.900 Well, here's a situation. If you take standard of care and you live 10 years, or like you said,

02:19:18.500 and you drop dead of a heart attack, was that heart attack the result of the cancer or the

02:19:23.980 treatment? You also have to put into perspective, what effect does the treatments have on your overall

02:19:30.160 long-term survival as well, right? So Dana Farber down here just opened up a branch of medicine 1.00

02:19:35.500 called cancer survivor medicine. It appears that many people treated with standards of care are

02:19:39.840 suffering from, horrifically, from all these other kinds of diseases they never had but for the fact

02:19:43.500 that they were treated with all this toxic stuff. So we would eliminate that. Why would you,

02:19:47.540 if you're in therapeutic ketosis and you're, it's unlikely-

02:19:50.400 But I'm still like, what's the proof of concept that the metabolic

02:19:53.480 therapy can lead to a cure? So is your hypothesis that this gentleman in Alexandria,

02:19:59.820 if he hadn't been, if he hadn't undergone radiation for the GBM, your belief is he could

02:20:06.180 have actually had a cure? I don't know because we can't know, like you said, we'd have to wait 10

02:20:11.200 years to know that. So if we were to institute an aggressive metabolic program for managing cancer-

02:20:17.500 But it seems GBM would be the place to do it, right? Because it's, you know, it unfortunately-

02:20:21.820 Unfortunately, it's such a uniformly fatal cancer.

02:20:24.660 And it's fatal because of the treatment that they're giving these, this combination of what

02:20:28.620 they're doing to the patient as well as the tumor.

02:20:32.060 The problem clinically, right, is that the mass effect doesn't give you a lot of flexibility to

02:20:39.440 delay surgery. So between corticosteroids and radiation, when a patient, some of most patients

02:20:45.440 present with GBM, not as incidental findings, they have symptoms from the mass effect. So

02:20:51.240 we have to be sympathetic to the clinicians in the conventional pathway who are saying,

02:20:55.760 look, I got Bob here. He's complaining he's got, you know, hemiparalysis and he's got a GBM.

02:21:03.360 The idea that we're going to wait a month to put him on a ketogenic diet when I need to either cut

02:21:08.160 that thing out now or radiate him or put him on corticosteroids. So in other words, this is going

02:21:13.980 to be a very difficult thing to study.

02:21:15.320 Well, it's a judgment call on the part of the neurosurgeon. Okay. So he looks at the data.

02:21:19.760 Do we have a watchful waiting period? This is, I've spoken to many neurosurgeons,

02:21:23.980 a lot of my friends. I said, what's the stat? What do we do here? He said, occasionally,

02:21:28.380 if you have brain herniation possibility, the patient will be dead in a week. We don't do

02:21:32.000 debulking. That patient has to be debult. All right. But you don't have to give them steroids.

02:21:36.660 You can just do debulking. Steroids will shrink the edema. 0.98

02:21:39.880 Yeah. Of the three, what would be the most evil in your mind? Meaning metabolically evil,

02:21:45.500 the radiation, the corticosteroid, or the surgery?

02:21:47.800 Oh, clearly the steroids and the radiation.

02:21:50.640 So then it would seem to me that every GBM patient should go and have the resection

02:21:54.800 and then undergo metabolic therapy, even though they're not technically going to be free of

02:21:59.740 disease. Yeah. I think this is the strategy. How long the watchful waiting period is will give the

02:22:06.060 neurosurgeon an opportunity to do a greater debulking? And there's a hundred articles in

02:22:11.020 the literature showing that the lot you live longer on debulking, the more you can debulk the

02:22:14.900 tumor. So if we can shrink the tumor down, like we did to the, on our Egyptian page, we waited three

02:22:19.780 weeks. We put them under incredible therapeutic fasting, water only, 900 ketogenic diet. They did a

02:22:25.840 very awake, good 900 calories, kilocalories. Yeah. But not water only, you said. Water for the first

02:22:32.380 three days, water only. I see. And then we transitioned him. He did an awake cradionomy.

02:22:37.540 It was done very well. Then we pushed off the radiation therapy for three months. And then they

02:22:42.740 did, and we didn't want to do that because the tumor was looking really good. He had a correction

02:22:47.260 of the midline shift. He was in good shape. So I think he suffered from the radiation. I think he

02:22:53.780 didn't survive because of the radiation treatment. Do you think that GBM would be the best histology to

02:22:58.960 study this in? Oh yeah. Because it's the, as you said, the survival is. You're going to see a signal

02:23:04.400 if one's there. Yeah. So, and then I've spoken to a lot of my friends who think that, okay, we have

02:23:10.120 to debulk immediately. Then we're going to go to metabolic therapy. We can push it off for two weeks

02:23:15.140 and then do metabolic therapy. The thing we have to do is we have to eliminate radiation. I think

02:23:19.640 radiation is part of the big, biggest part of the problem. I think when you do, if you're doing

02:23:23.420 metabolic therapy, you should eliminate radiation right away. I have no doubt about this. This is

02:23:27.720 absolutely, in my mind, a problem. And this is one of the reasons why there's so few people

02:23:33.300 surviving. It's because you are radiating this. If you didn't irradiate, you could survive a lot

02:23:37.860 longer. I think with metabolic therapy, you can double, triple the amount of survival. How do we

02:23:42.620 know this? Because those patients that I know who rejected radiation and chemo, took surgery after two

02:23:48.260 years, a year, are doing well. They're out four years. So clearly- With which histologies?

02:23:53.280 GBM. There are GBM patients alive? Yes. At four years? Yes. Pablo Kelly. In fact,

02:23:59.600 I'm going to be there next week. He's going to be sitting in the audience. Is this published?

02:24:03.020 No, it's not published, but the guy has all the documentation. It's just that it's not yet

02:24:06.860 published. Why? Because I haven't sat down and wrote it up yet. What would be more important than

02:24:12.340 writing that up? Writing another paper up that I thought the guy was going to live just as long,

02:24:16.240 but he was already- No, no, no, no. Look, that guy was one guy alive three years. If you have a cohort of

02:24:21.260 patients that have been alive for four years with GBM, I don't know what would be more important

02:24:25.720 than writing that up. Do I? I don't know of anything more important either, but you don't

02:24:28.800 forget- We should stop this podcast now so you can start writing that up.

02:24:31.660 Well, I'll talk to him. In fact, he's going to be giving a lecture after my lecture.

02:24:36.320 Because that's, I mean, that's really where you want to be able to generate interest on a clinical

02:24:39.720 trial. Okay. So how many people, he's a young guy, 25 years old. He says, I don't want radiation.

02:24:45.040 I don't want chemo. I don't want any of that stuff. I don't want surgery, he says. Oh, you're going to be

02:24:49.360 dead in three to six months. That's what they told him. It's all in the news. It was in the 0.97

02:24:52.360 newspapers. I gave him the stuff on the metabolic therapy. I didn't know he was going to live that

02:24:56.480 long. I thought he was just going to live a few extra months. He comes back and he says,

02:25:00.400 I'm still alive. And there's a big newspaper article in the British newspapers about this

02:25:03.660 guy who rejects all. So after two years, he had an inoperable glioblastoma that now became

02:25:11.120 operable after metabolic therapy. So they debulked it. And now after another year, he doesn't have any

02:25:17.800 tumor left. And he never had radiation. He never had chemo. He had surgery very delayed.

02:25:23.680 And they did a histological analysis after the debulking, said, yes, you did have a GBM.

02:25:28.000 Because what a lot of people say, if you've lived that long, you never had a GBM. 0.99

02:25:31.680 That's bullshit. The problem is just that, I mean, you're creating a situation that leads to the demise 0.93

02:25:40.120 of those very people that you are trying to help. And when you irradiate the brain,

02:25:45.020 you free up massive amounts of glutamine by breaking the glutamine glutamate cycle. So those

02:25:50.480 tumor cells are sucking down massive amounts of glutamine. And then you give the steroids to

02:25:54.500 reduce the edema, which then elevates the blood sugar.

02:25:57.000 So I was going to give you two experiments, two dream experiments. So the second one would be

02:26:01.640 going back to sort of the more fundamental premise of this, which is what if resources were,

02:26:07.900 you know, no constraint, how could one unambiguously make the case slash test the hypothesis

02:26:16.080 that despite structural abnormalities in the mitochondria, the production of lactate and the

02:26:24.620 fermentation is not purely for respiratory compensation. In other words, we talked about

02:26:30.960 this idea that says you can have a structural deficit, but still be functionally good enough.

02:26:36.380 How can that hypothesis be tested? Because that seems to be one of the central arguments here.

02:26:43.120 Well, I mean, there's several ways we look at this. If a cell can live with ketones without

02:26:47.400 glucose and glutamine, you'd obviously have some mitochondrial function that would keep them alive

02:26:51.580 because they wouldn't be able to ferment.

02:26:53.100 But let's like, we're in a resource unconstrained world. So what are the dream experiments that would

02:26:57.860 test that in humans?

02:27:00.500 I mean, in vivo, because a lot of these mechanisms would be tested in vitro because you can't do those.

02:27:06.360 kinds of experiments. But the metabolic therapy that we have designed, Dom DiAgostino, myself,

02:27:13.580 Joe Maroon, who's the team surgeon for the Pittsburgh Steelers neurosurgeon, George Yu,

02:27:18.200 who is a prostate oncologist, prostate cancer oncologist. We all sat down and we built this

02:27:24.200 press pulse therapy. Okay. So if you deprive the tumor cells of their fermentable fuels

02:27:29.800 and you kill, and you essentially eliminate, I can't detect any more cancer in your body.

02:27:35.960 That's based on the biology of what the problem is. All right. So the dream experiments are to

02:27:42.700 ferret that out mechanistically in vitro. So to prove that this is the case, and we're doing that

02:27:47.220 right now when we target these things, these cells die. So you can put them in where normal cells

02:27:53.120 wouldn't die. So clearly what's going on here? I mean, it was shown in many papers. In fact,

02:27:58.460 back in the 30s and 40s, beautiful papers showing that the respiratory system of tumor cells is

02:28:03.520 massively compromised. Okay. If that's the case, then they're surviving on fermentation. There's no

02:28:08.940 other known biological system in the world that can provide alternative ATP.

02:28:15.200 But yet most people don't agree with that statement. So that's what I'm asking is what

02:28:18.540 experiment could take the debate out of that very important question?

02:28:22.160 Okay. So they don't believe it. If I look at the data and you look at the data and we both come

02:28:28.220 to the same conclusion, and this other guy looks at the same data and he says, I don't believe it.

02:28:32.420 Then it tells me the data are not convincing enough if everybody's acting in good faith.

02:28:36.300 Well, then you have to ask about what's good faith. If I have-

02:28:40.220 Or what's better data.

02:28:41.100 Okay. Look, here's the way I look at it. If science is a human activity, okay, there are people who say

02:28:47.840 things that are not true and everybody believes it. Right? Right? All right. So I look at something

02:28:53.280 and but I don't-

02:28:54.280 I'll refrain from making all political jokes right now.

02:28:57.540 Yeah, right. Right. I understand. But I understand completely. But the issue here,

02:29:02.320 of course, is that you have, it's one thing to say, okay, we had a review on a paper that we know

02:29:11.640 there's a massive biology on the role of cardiolipin in controlling the electron transport

02:29:15.340 chain. I mean, there's dozens and dozens of papers on this. And a molecular biologist,

02:29:19.260 I don't believe it. Well, what don't you believe? What part of this massive amount of scientific

02:29:25.060 evidence that you don't believe? I'm unfamiliar with cardiolipin, therefore it can't be right.

02:29:30.800 Well, that's not the reason to discount them. Right, right.

02:29:33.760 And when you write the paper up, why would you not cite Pete Peterson's massive compendium

02:29:38.600 of evidence saying mitochondria are abnormal? And you say mitochondria is normal. Well,

02:29:43.000 how does that jive with the massive amounts of evidence to say that's not-

02:29:48.520 What I try to do in all my writings, I never try to ignore an alternative fact to what I'm saying.

02:29:56.360 I try to say there is a fact that I'm not yet completely clear about, but I'm not going to

02:30:02.920 ignore it, okay? You'll find in the scientific literature today, in the top journals, that

02:30:08.620 they're ignoring massive evidence that don't support their position. And that's one of the

02:30:15.020 problems. And like, you know, we were saying that this problem in cancer, all these top journals

02:30:19.880 sell science nature. You know, 50% of them, up to 50% of the article can't be reproduced in

02:30:25.240 other people's labs. This is a crisis in the field. What's going on here? So you're ignoring

02:30:30.500 massive evidence that doesn't fit your particular mindset. So you will just discount it. I don't

02:30:37.100 think it's any different than the geocentric, heliocentric model of the solar system. The

02:30:42.500 Catholic Church refused to believe that the earth was not the center of the solar system,

02:30:47.160 despite all the evidence that said it was. They just refused to believe it. We have the exact same

02:30:52.320 thing in the cancer field. You have massive evidence showing that the mitochondria are

02:30:56.160 structurally and functionally dysfunctional. I don't want to believe it. What can you do about

02:31:03.500 that? What can you do about that when you have the evidence to show that and you choose not to,

02:31:08.480 you choose to ignore it? Is that any different than the heliocentric, geocentric system that we

02:31:12.860 had? The difference today is that we have 1,600 people.

02:31:16.180 Yeah, I mean, it's slightly different, right? But I don't want to get into the details.

02:31:19.100 It's a fact. You have fact. And don't forget, they didn't-

02:31:22.460 Well, but I think the Catholic Church was basically relying on a religious framework

02:31:28.160 as their counter-argument.

02:31:30.280 Of course.

02:31:30.720 And so their belief system was formed by something different. I think in the scientific-

02:31:35.760 Yeah, but when Galileo said, please look through the telescope to document that Copernicus was right,

02:31:40.900 they didn't want to look in the telescope. They didn't want to look in the telescope.

02:31:44.140 So because it would disrupt their worldview. If you've just put the list-

02:31:48.380 No, I mean, I think that's a fair statement. I guess, again, I come back to this through the lens

02:31:53.520 of I'd love to know what the experiments are that could- because I view it as a stalemate. If you're

02:31:59.120 looking at a body of literature and they're looking at a different body of literature and every time

02:32:02.160 everybody looks at everybody else's body of literature, they say, well, there's an alternative

02:32:06.680 explanation for this, then we're making no progress. The answer to me is collaborate,

02:32:12.200 generate new experiments where-

02:32:15.340 Well, that's why I think knowing the biology of the diseases as well as I think I do, and we never

02:32:20.600 can know completely everything because every human being is a different entity. You're dealing with

02:32:25.020 a different entity. If we can increase overall survival and improve quality of life, massively

02:32:31.720 advanced to what we're doing today, because we use the strategy based on what we understand to

02:32:37.820 be the biological problem and the results support that, then I think that's the advance. And

02:32:42.960 glioblastoma would be a wonderful-

02:32:45.220 So speaking of that, realistically, when do you think that case report of these four years

02:32:50.100 surviving cohorts will be published?

02:32:51.680 I'm going to try it. When I talk to him over there, I'd like to speak to the very physicians

02:32:54.880 that actually took the data from him, from Pablo.

02:32:58.360 How many patients are in that cohort?

02:32:59.860 Just him.

02:33:00.360 Oh, there's just one guy who survived four years.

02:33:02.400 Well, one guy because he rejected-

02:33:04.120 No, I understand. I misunderstood. I thought there were several patients.

02:33:06.720 Well, there's Andrew Scarborough who initiated a first couple of radiations and said, no more

02:33:10.860 of this. He took no radiation, no chemo. He's still going. He had a stage three astrocytoma,

02:33:16.340 which is also quite lethal. Then there's Alison Gannett. She's on the news. She has a website

02:33:21.320 saying that she survived GBM without this. I have other anecdotal reports based on what people

02:33:27.980 have told me. One poor guy, he had no money, no insurance, so they didn't want to rate it because

02:33:34.460 they wouldn't be able to rent any revenue from this guy. He just did ketogenic diets way back

02:33:39.960 before even I was talking about it. He's still alive 16 years.

02:33:43.120 But what was the, did they eventually do surgery on him?

02:33:48.760 They did surgery, but they didn't do anything else.

02:33:52.040 So what is it?

02:33:52.700 So again, these are anecdotal, but with Pablo, we have data. We have clear data from him.

02:33:57.460 So it's not like we don't have data from him. You know, we have a lot of things, a lot of these

02:34:02.900 things people would say, well, you can't do this. You can't do what I'm asking you to do because

02:34:07.740 it breaks the, it violates the standard of care. Okay. The standard of care should never have been

02:34:13.620 written in granite. It should be flexible. If you have something else that comes along that might be

02:34:18.020 better, you'd think there would be an enthusiasm. No, we have not seen that. We try to get this

02:34:23.640 through the University of Pittsburgh to try to do this. The advisory board, right? The IRB.

02:34:29.080 The IRB refused. Okay. So they would only, might consider metabolic therapy after standard of care

02:34:35.960 fail. Well, standard of care fails all the time. Why don't you try metabolic therapy as an

02:34:39.720 alternative to stay? Oh, no, we can't do that. Why? Well, because we can't do that. Why? Because

02:34:44.920 we can't do that. That means there's inflexibility. So we're up against firewalls after firewalls after

02:34:51.520 firewalls to try to change the way we continue. We're doing all the gene screening, mounting to

02:34:57.420 nothing because cancer is not a genetic disease. So we have all these firewalls that are preventing us

02:35:02.200 from moving forward the way I think we need to be moving forward. For a GBM patient, what do they

02:35:06.560 have to lose? There was a paper that just came out the other day and from out of British Columbia,

02:35:11.300 Canada, looking at, carefully looking at survival for GBM. They said it's woefully similar to the

02:35:16.800 1926 Bailey and Cushing paper for Christ's sake. I mean, what's going on here? You mean an 100,

02:35:21.540 almost 100 years? John McCain's size 12 months. That's no different than if he had the cancer,

02:35:26.240 than if he had the tumor in 1926. So that tells us we have a serious, serious problem and I'm

02:35:33.680 offering an alternative that might be able to change that. What is wrong with that? Why would

02:35:40.080 I be attacked for something like this? Right? So you tell me, I have to know what's going on here.

02:35:45.220 So I go up and I say, you can't irradiate the brain. Oh, you got to do it.

02:35:48.400 Here's my parting shot of advice, Tom, which is it's worth nothing, but your passion is palpable.

02:35:55.400 I lost a friend to GBM. So the very first person in my life that I ever knew that died of cancer

02:35:59.920 died of a GBM. And I was with him almost until the day he died. And it was the saddest thing to

02:36:05.720 see the last year of his, he lived 18 months and a year of it, he didn't, he couldn't see.

02:36:11.160 So, you know, talk about what is it like to be a 19 year old kid who can't see anything. And I look

02:36:18.160 at, uh, it's actually one of the saddest stories of, I don't even want to tell it. It's so upsetting.

02:36:21.660 Anyway, um, I get it. I think my advice would be the following, whatever you've been doing a,

02:36:28.000 the phone rings. What the hell? Perfect time. Um, whatever you've been doing is not getting 0.70

02:36:32.260 through. You got to do something different, right? So there's, there's a quote by someone who's

02:36:36.620 escaping me. It's like the definition of insanity is doing the same thing over and over again,

02:36:40.080 expecting a different outcome. You got to do something different. Well, I don't know what it

02:36:44.180 is. If I had that advice, I'd offer it, but, but I'm just saying you've got to try a new

02:36:48.060 approach to get that clinical trial done. Yeah. Well, you know, don't forget I'm a professor

02:36:52.060 at a, in an academic non-medical school environment, right? So we ferret, we, we design

02:36:57.120 the preclinical studies that allow the clinicians to then adapt it to their patient population.

02:37:03.460 So this is what there's very, we're the only, one of the only groups in the world that are actually

02:37:08.200 doing bench to bedside real research, because I have, I have tentacles for all these different

02:37:13.640 clinical things. It's, it's, I get it. All I'm saying is the current, you're, you're, you're

02:37:19.660 abutting a resistance and I, you've got to go around it. You've got to, you've got to find a

02:37:25.380 way to go around it. And it might be that you get enough of these case reports published that it

02:37:30.800 becomes very difficult to ignore. And people would say, look, you know, here's a concession.

02:37:35.640 We're going to do surgery immediately and then follow with metabolic therapy. Cause I think you're

02:37:41.120 going to have a very hard time saying no surgery, no corticosteroid, no radiation. I just don't,

02:37:47.040 I think that's metaphysically not going to work. No, no, no, no, I know. That was a judgment call

02:37:50.020 on the part of the, on the part of the clinician. But, but I'm saying if you're, if you're willing

02:37:53.580 to accept immediate surgery, but delaying or postponing radiation and or corticosteroid therapy

02:38:01.740 until they are necessary, either due to medical progression and or symptom control, uh, you have a

02:38:09.020 chance. And so of course the question then is you, you've got to find advocates on the other side of

02:38:13.900 this ledger, meaning, but the ledger meaning in terms of the thinking about this disease.

02:38:18.480 Yeah. Well, I agree with you. I mean, and so what would you suggest? What's the, what's the end

02:38:23.060 game? What's the roundabout approach? What you're, you're in the field. I mean, you're a great

02:38:28.580 discussion over that scotch that you promised me before we started this podcast.

02:38:32.720 See, see, so we're trying to, we're trying to do this, right? And we need guys like yourself and

02:38:40.240 others to get the word out that there are alternatives and that who's going to be the

02:38:44.420 bold one. And I know I'm speaking to now people who want to set up these special clinics, special

02:38:49.240 kind of treatment clinics where we can bring everything under the same roof. So you don't

02:38:53.180 have to run over this place in that place. We take the patients, this will happen. It will happen

02:38:57.760 because people want to live. Yeah. Look, I mean, that was going to be my, if, if, if forced to

02:39:02.400 give one idea now, cause I don't, I don't think I know the answer, but if I were going to give you

02:39:06.280 one suggestion, it would be do this from a position of pull, not push. So right now you are pushing

02:39:13.320 this idea. What you really want to do is take a page out of the Charlie foundation where they're

02:39:19.000 basically saying, look, in the end, the results were so dramatic that the parents of the children,

02:39:24.780 a third of whom now no longer suffer from epilepsy, another third of whom have at least a 50% reduction

02:39:31.320 in epilepsy. They basically become the voice of reason. And I think that's a part of the reason

02:39:36.500 today. Not the only reason I think the data are so good, but I think they're a part of the reason

02:39:40.840 why today the only place in sort of the traditional medical view where a ketogenic diet is viewed as a

02:39:48.340 legitimate first line therapy for, you know, recalcitrant disease is in epilepsy. Now I think

02:39:55.000 there'll be a day when that expands. So what I, what I, what I would hope is that there's a network

02:40:01.040 of people, family members, probably who have lost people would to GBM who would, would become the ones

02:40:08.480 that would be your mouthpiece, right? Would become the ones that would say, you know what? I'm tired of

02:40:12.840 the fact that my loved one died in nine months, seemingly in vain. And there's this, there's this

02:40:19.440 body of evidence, which look, admittedly at this point is small and is uncertain, but nothing in

02:40:24.500 science is certain, but they're offering an alternative. I want to know that that could be

02:40:29.040 tested. Yeah. And the thing that it kills me on these private foundations and things, their advisory

02:40:33.820 boards are made up of physicians that subscribe to the gene theory of cancer. So when the patients

02:40:39.060 and their advocates here, here's my second piece of advice. I know I said, I wasn't going to give

02:40:42.820 you any advice. My second piece of advice is you're fighting an uphill battle. You don't need

02:40:46.720 to, it, it could be a genetic disease and a metabolic disease simultaneously. I would argue

02:40:51.320 that cancer is when you think about the three diseases, the three disease processes that are

02:40:55.960 going to kill all of us sitting here right now in this room, it's going to be atherosclerotic

02:41:00.500 disease, neurodegenerative disease, or cancer. Statistically speaking, that's how we're going

02:41:05.880 to die of those three. I don't think there's any that are more evolved and complicated than

02:41:11.400 cancer. I think cancer is by far the hardest of those. And therefore, there's where I would

02:41:16.600 disagree. Well, but that's too long a discussion. The point is whether you agree with me or not,

02:41:21.320 let's argue the following, or let me state the following and or posit the following.

02:41:26.380 It's a very evolved condition. And therefore you could have genetic pressures, metabolic pressures,

02:41:33.560 immune pressures that all predispose to it. So I don't think it has to be an either or.

02:41:38.160 I think metabolic therapies could be valuable whether or not the genetic ideas of cancer are

02:41:43.320 right or wrong. So to me, it strikes me as an unnecessary fight, right? Instead, the answer

02:41:48.560 should be, look, we should have medical oncologists, radiation oncologists, surgical oncologists,

02:41:53.340 immuno-oncologists, and metabolic oncologists, period. Now you might argue those radiation oncologists

02:41:59.120 are causing more harm than good. That's beyond my pay grade. You might be right. But you're basically

02:42:04.120 arguing for a fifth branch of oncology, which is the medical oncologist above the three that we

02:42:09.760 conventionally have. I think the immuno-oncologist is coming into his or her own right now. I don't

02:42:15.020 think it's worth arguing about whether it's a genetic disease or metabolic disease. It's just

02:42:18.360 a goddamn hard disease. And we need every therapy imaginable. And sometimes that will be doing things 0.99

02:42:24.100 that are completely new as you've proposed. So anyway, on that note, I want to thank you very much

02:42:30.520 for your generosity of time and just your passion for this and sort of how tirelessly you've worked

02:42:36.800 on this. I mean, this is only our first time meeting today, Tom, but I've been familiar with

02:42:40.720 your work for probably eight years now, which is a small fraction of the amount of time you've put

02:42:45.460 into this. Dom is a very close friend. And so through Dom and through Bob, I've learned a lot more

02:42:50.860 about your work. And I know that a lot of people listening to this are going to be rooting for you

02:42:54.860 to do this. Is there anything that someone who's listening to this, who's got a loved one who's

02:43:01.840 either died of GBM or has GBM, that they can do to increase the chances that either others can get

02:43:10.360 the types of therapies you're talking about in clinical trials or that their loved ones themselves

02:43:15.240 can? What else can they do? Well, I mean, in my position as a researcher who does the preclinical

02:43:20.800 studies, I mean, we get support from Travis Foundation, you know, the Metabolic Therapy

02:43:25.540 Foundation. And that's what keeps our program going. And that's what tells us what we think

02:43:31.780 should work really well or what might not work to help these people get the outcome that they want,

02:43:37.880 which is high quality of life and living a lot longer. So my big thing is that. In other words,

02:43:45.400 we can identify those. And where do you do that? You need funds for that. And the federal

02:43:50.060 government is mostly like what gene is involved. So this is where it comes back to the same problem

02:43:54.540 again. You don't get funding for things that actually can really work versus studying the

02:43:59.440 disease. Let's look at the meta. Let's study the disease more. We don't need that. We know we have

02:44:03.500 a path. We have a clear path. So is there an easy path for patients who want to make financial

02:44:08.220 contributions to the lab? Is it through a foundation that is the easiest? Yeah, well, there's two ways to do

02:44:12.120 it. You can either do it through the foundation because we have a continual grant set up through

02:44:16.180 single cause, single cure foundation. Okay. So we'll link to that to make sure that people know

02:44:20.600 what that is. And also at Boston College, if you want to fund the work directly through the

02:44:25.020 university, it has to be through a very specific statement. Otherwise, the university will absorb

02:44:31.280 some of the other funds. So basically, that's the way. Now, what we do then is our data are immediately

02:44:38.220 given to the clinical people who then put it on their patients and then feed me back and say,

02:44:43.720 this is working well, or we don't think this is doing as well as we should. Why don't you tweak

02:44:47.640 it in this direction? So I work with the physicians directly and I give them the preclinical information.

02:44:53.520 They feed me back and see how it's working. Sometimes it works a hell of a lot better in

02:44:57.040 the human than the mouse. So let's be sure that we have from you any and all means that people who

02:45:02.720 are passionate about this, interested in this, either personally or through sort of indirect

02:45:07.200 experience can support this work. And more importantly, I think, create maybe a bit of a groundswell

02:45:13.360 that puts a little bit of pressure on the IRBs to say, look, this is, you know, GBM is as high

02:45:19.160 stakes as it gets, right? It's the type of cancer that gives cancer a bad name. And maybe this is

02:45:24.800 one area where we have to increase our appetite for risk in clinical trials.

02:45:29.920 I agree with that. And I think that this is a disease that we think we can make major advances

02:45:34.580 in and why not want to give it a shot? Because it's not going to hurt anybody. It's not going to

02:45:39.200 accelerate their demise. It's only going to-

02:45:41.100 Well, I mean, I would disagree with that only in terms of a talking point to say it could.

02:45:45.000 We don't know. But that's the point of risk, right? I mean, when the outcome is so asymmetrically

02:45:50.920 bad, which is uniform death in an accelerated fashion, we have to be willing to take the risk

02:45:58.260 of potentially doing worse than that. I don't think that's the case.

02:46:01.460 I've never seen it.

02:46:02.280 I understood. But I think the way we talk about this, when we talk about this as though 0.98

02:46:06.960 there's no risk, I think that reduces our credibility with people who say, well,

02:46:12.220 how can you say that?

02:46:12.960 Well, any open cranial surgery produces risk.

02:46:16.520 Yeah, that's the point.

02:46:17.560 And that's going to be a part of all what we're doing.

02:46:20.520 Well, the point is, you know, Bob's heard me rail on this many a time. This sort of idiotic 1.00

02:46:26.680 idea of a Hippocratic oath, which is technically he didn't even say it and it's such a dumb thing 1.00

02:46:30.520 anyway. First, do no harm. I mean, you couldn't do any good if you weren't at least willing 0.51

02:46:34.420 to do some harm. No one goes into it wanting to do harm. But anyway, this has been really

02:46:40.140 exciting and I really appreciate your time and your insights and above all else, the work

02:46:44.760 you've done. So thank you, Tom.

02:46:45.860 Yeah, thank you.

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The Peter Attia Drive - November 26, 2018

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

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