Introduction: Coming up on this episode of The Doctor’s Pharmacy …
Dr. Thomas Seyfried: Cancer is a disease of Western diets and lifestyles, because it never existed, nor does it exist in our closest primate relatives, the chimpanzee, which is about 98.5% similar to us in gene and protein sequence.
Dr. Mark Hyman: Welcome to Doctors’ Pharmacy. I’m Dr. Mark Hyman. That’s a pharmacy, a place for conversations that matter. And if you’ve had cancer, or anyone you’ve known or loved has had cancer, I think this is going to an important podcast, because we’re going to talk about a very radically different view of how to approach cancer treatment beyond the usual slash, burn, and poison. Cancer is one of those diseases that is on the rise, not on the decline, and we’re really not that far ahead of where we were 50 or 100 years ago. We have some good treatments like immunotherapy, CAR-T therapy, checkpoint inhibitors, which are a great advance. But we’re going to talk about something quite different, which is the approach of using metabolic therapy or metabolic oncology today with one of the world’s experts in this field. And we’re going to talk all about metabolic health, metabolic treatment of cancer, what that means, and how we can really potentially get a leg up on this horrible condition that is affecting so, so many people.
Today we have as our guest an incredible scientist, Dr. Thomas Seyfried. He’s an American professor of biology, genetics, and biochemistry at Boston College. He received his PhD from the University of Illinois, [inaudible 00:01:32] in 1976, and he did his postdoc fellow at Yale University School of Medicine. He’s written over a 50 peer-reviewed publications, and his research focuses pretty much on the underlying mechanisms driving cancer, as well as things like epilepsy and neurogenic diseases, and how we may be able to use food, believe it or not, calorie restricted ketogenic diets to prevent and treat cancer. He’s the author of an incredible textbook that’s not a light read, so it’s not a book you want to get unless you’re really willing to go into the science. It’s called Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. And he’s currently on editorial boards of many journals, including Neurochemical Research, Nutrition Metabolism, the Journal of Lipid Research, and ASN Neuro. And welcome Dr. Seyfried.
Dr. Thomas Seyfried: Well, thank you very much, Mark. It’s a real pleasure to be here and have this opportunity to discuss some of our views on the origin of cancer with you.
Dr. Mark Hyman: Thank you. Well, my father died of cancer, my sister died of cancer, and I had cancer twice, so I’m very interested in this subject. I see so many patients with cancer. So many of my friends and colleagues reach out to me with looking for a Hail Mary on cancer treatment. It’s one of those horrible, horrible conditions that we haven’t made a whole lot of progress on. We think we’re a little bit better at early detection, we’re a little bit better at some of the chemo regimens. We’ve gotten advances in certain areas like immunotherapy and CAR-T cells and things like that, but they don’t work universally, and we still have a lot to learn about how to use those therapies.
The question is, is there a different way of thinking about cancer? Is there a different way of looking at how to understand the origins of cancer and cancer metabolism as a way of coming up with a radically different approach to treating cancer? You’ve been doing this work for 30 years now. It’s pretty much an accepted form of research and thinking. But when you started, it was kind of heresy. I remember not too long ago, I was with Siddhartha Mukherjee, who was an oncologist who wrote the Emperor of All Maladies, won the Pulitzer Prize for that, is a leading cancer oncologist, researcher, and thinker. He now was doing his work really primarily on using ketogenic diets to treat cancer. When I saw him once at a conference, he says, “Mark, I think we finally figured out what’s the problem causing so much cancer.” I’m like, “What’s that?” And he’s like, “Sugar.” And I’m like, “Oh yeah, of course.” And we know that people who are overweight have a higher risk of cancer, people with diabetes have a higher risk of cancer.
This is actually something you’ve been working on for 30 years, and I’d love to walk back to the origins of this idea, which arose early in the 1900s from a scientist named Otto Warburg who talked about the Warburg effect. He was a guy whose theory caught hold a little bit, but was mostly discredited and ignored, and still sort of on the peripheral of medicine. But you’ve taken his work to the next level, and I’d love you to talk about what is the metabolic theory of cancer, and how did Otto Warburg [inaudible 00:04:49] process, and where have we come since then? Let’s have you unpack some of that.
Dr. Thomas Seyfried: Yeah, okay, great. Well, thank you very much. These are really important points in our understanding of cancer, where we’ve been and where we are and where we need to go, actually. Well, in my science training over the years, the word Otto Warburg really was mostly in the background. I didn’t really know what he had done in any meaningful way as trained geneticists and biochemists. When we started our work in epilepsy at Yale University, we were working predominantly on glycobiochemistry of epilepsy. I even tried to write a grant on ketogenic diet for epilepsy at Yale back in the 1970s, an internal grant. And they basically said, “Forget about it. Nobody cares about ketogenic diets for epilepsy.” It was Jim Abrams from Hollywood whose son Charlie almost died from standard treatments for his epilepsy, and Jim started the Charlie Foundation using ketogenic diets. One of my students at that time, that was late in the mid 1990s, said, “Oh, there’s a real excitement about this ketogenic diet.” I said, “Forget about it. Nobody’s interested in ketogenic diet.”
Dr. Mark Hyman: I mean, how could food have anything to do with disease, right?
Dr. Thomas Seyfried: Yeah, right. After my experience at Yale, I said, “Wow, these guys down here, they don’t care about …” So anyway, she went out there, came back, “Oh man, everybody’s excited about this ketogenic diet.” We had developed really some excellent models of epilepsy in our lab. We were trying to figure out mapping genes for epilepsy, and doing all this kind of stuff. She came back, Mariana [inaudible 00:06:51], and said, “Let’s try ketogenic diets on epileptic mice.”
And at the same time, we had been doing a lot of work in cancer, but it was mostly biochemistry. It was like traditional biochemistry. It was no translational benefit to the clinic about most of what we were doing, other than trying to … We had two parallel projects. One was epilepsy, one was cancer biochemistry. And then we started treating our really good model of epilepsy with keto, with calorie restriction and restricted ketogenic diets. It all came down to the lower the glucose, the better the seizure management management was on this.
So some guy came in, a company that was interested in a drug, 60 Oxy. NBDNJ, it’s a kind of a drug. And we found out that if you feed it to the mice, their seizures went away, and said, “Wow, this is really exciting.” But we fed it to the mice with cancer, and all of a sudden the tumors went down as well.
Dr. Mark Hyman: Wow.
Dr. Thomas Seyfried: So we said, “What’s going on with this drug?”
Dr. Mark Hyman: This is a drug also known as DON, right? DON?
Dr. Thomas Seyfried: No, no, no. That wasn’t done. This was [inaudible 00:08:11]. It’s kind of a glucose analog of some sort. And it was having an effect on epilepsy, at least in preclinical models. But we tried that drug on some of our cancer mice, and we found also that it seemed to reduce tumors, the same drug that we had for epilepsy. I said, “What’s going on here with this?” And it turns out that the drug blocked sucraces in the gut, so the animals would eat the food, but they couldn’t digest the food, and their blood sugar went down.
The drug company at that time thought we had a blockbuster drug for cancer because it was shrinking tumors, but the mechanism wasn’t known about how that worked. Then when we found out that well, the animals were eating food, but they were losing body weight and the tumors were shrinking. We said, “What the hell’s going on with that?” Then when I put in a control group of mice, feed them until their body works, cut their calories down until the body weight of the control mice not getting the drug and the mice getting the drug were the same. And we found that the tumor shrunk just as well in the control guys as it did in the drug treated guys, and the drug was simply preventing the mouse from eating the food and digesting the food, and the blood sugar went down.
When I told the company that this drug was working through calorie restriction, they dropped the project immediately. They didn’t want any part of this. They want to move on now. “We want drugs that are going to …” I says, “Yeah, you can get the same effect if you restrict calories.” You find out how fast people are. They’re all excited until you realize what the mechanism is, and then when you realize all you have to do is just cut calories and get the same effect, that wasn’t exciting.
But we were excited about it and we thought, “What is the mechanism by which calorie restriction have such a powerful effect on reducing cancer?” Brain cancer in particular. And then we started to hear about Warburg, and he was saying the tumor cells are dependent on glucose, and these drugs block glucose, and the calorie restriction blocks glucose. So we started to then bring in what Otto Warburg was saying for a long time. Then we started to do the mechanism of action. And what we found was diets that would reduce blood sugar and elevate ketone bodies, which is an evolutionarily conserved adaptation to food restriction … We all go into ketosis if we stop eating food for a long enough period of time. Our brains have to have some level of energy. And what happens is the blood sugar goes down, you start mobilizing fats, they go to the liver and you make water soluble ketone bodies that go to the brain and allow the brain to burn energy in the presence of low glucose. And other tissues, the heart as well.
We were looking into all of this stuff, and we found that calorie restriction is powerfully anti-angiogenic, which means the abnormal blood vessels and tumors are really hammered. And that at that time in early 2000-
Dr. Mark Hyman: And the tumor cells need the blood flow in the blood vessels to go there [inaudible 00:11:40]?
Dr. Thomas Seyfried: Yeah, they’re abnormal too. The blood vessels are leaky, they’re abnormal. And that was thought to be provocative to the growth of the tumor. And as you know, during the early 200s they were coming out with all these anti-angiogenic therapies from the pharmaceutical industry, many of them which don’t work. We found out why they don’t work for the most part. But at that time, it was a hot area. Anti-angiogenic therapy was like, Judah Folkman and a lot of well-known people were saying how powerful these anti-angiogenic therapies. Napoleon Ferrara, who later come out and said, “Most of them don’t work.” A lot of them were pulled off the market for all these adverse effects. Some of them are still on the market, which to me makes no sense at all.
But any event, it was a hot area. And we showed the calorie restriction could be as powerful or more powerful than anti-angiogenic. And then we did some really good mechanistic work on inflammation. NF Kappa B inflammation was targeted by calorie restriction, and then the cells were dying through a variety of mechanisms. Tumor cells were dying. The microenvironment was becoming much, much less inflamed. Angiogenesis was going away. And I’m saying, “What the hell? This calorie restriction is really powerful.”
And we were doing it in the mouse, and then we realized, “What does calorie restriction mean in the mouse to a human?” And then when we compared the differences in basal metabolic rate between the mouse and the human, we realized that the human could get the same effects as this calorie restricted mouse, only if they did water-only therapeutic fasting. Well, nobody wants to hear about that, let’s be honest. I mean, oh, well, who’s going to go out and do all that stuff? But we started to look more and more into the mechanisms of action by which calorie restriction. And then with our knowledge of ketogenic diets, I said, “Why don’t we consider shifting just water-only fasting to calorie …” Because that’s ultimately what Wilder found in the 1920s for managing epilepsy. He said, “People with epilepsy who went on water-only fasting, invariably their seizures would go away.” But it wasn’t a sustained way to treat epilepsy.
Dr. Mark Hyman: No.
Dr. Thomas Seyfried: So he developed a ketogenic diet as a prolonged way of treating epileptic seizures. So I said-
Dr. Mark Hyman: [inaudible 00:13:55] calorie restriction, right?
Dr. Thomas Seyfried: Yeah.
Dr. Mark Hyman: When you’re fasting, your body starts to burn fat from your fat stores. So it’s a survival mechanism, and we end up having the ability to actually burn fat, which mimics calorie restriction.
Dr. Thomas Seyfried: That’s right. And what you do is when you water-only fast, your blood sugar goes down and your ketones go up. And then Wilder said, “Why don’t we get a diet that will make blood sugar go down and ketones go up?” And that was a ketogenic diet, but it was quite on palatable and at the time. But I said, “Let’s try that same concept with cancer.” Some people had dabbled with that in the past, but not in a serious way. We launched a much more aggressive and serious evaluation of how we can move someone from water-only fasting into another therapy that would have a similar benefit.
And then of course, Otto Warburg’s concepts came in, and I looked at what Warburg had said, and we started getting some of his German papers translated into English. I read all of his major papers. His argument was that in cancer, there is some defect in the ability of the mitochondria in the cell to produce energy, which is the way most of our cells get energy. We breathe oxygen, and oxygen serves as the final common acceptor of electrons in our mitochondria to generate energy through oxidative phosphorylation. And he said, “That’s broken in cancer. And in order for the cancer-”
Dr. Mark Hyman: Wait, slow down for a sec. What you basically said was, in order for us to produce energy in our cells, most of us combine oxygen with sugar in this kind of chemical reaction down in assembly line called oxidative phosphorylation. It’s the normal way you produce energy from food, and it’s through glucose primarily, and oxygen. That’s what you’re talking about. [inaudible 00:15:46].
Dr. Thomas Seyfried: Yeah. We bring glucose into the cell, or other foods that would be broken down either into glucose or acetyl-coa, which is the end product of the glycolytic pathway. The cell brings in glucose. There’s a 10 step pathway called glycolysis, the old The Embden-Meyerhof-Parnas pathway. And then the pyruvate, which is a three carbon derivative of glucose, then enters into the mitochondria and is fully oxidized to produce significant amounts of energy, with the key waste products being water and CO2. Every time we exhale, we’re exhaling the waste products of food metabolism, which is CO2 and the moisture water. We can develop urine from combining with amino acid breakdown products. It’s a very highly energy efficient system.
But Warburg was saying that cancer cells have a defect in their mitochondria, and that defect is compensated for by a upregulation of these ancient glycolytic fermentation … Glycolysis is present in all of our cells. The problem is when the mitochondria become defective, the end product of glycolysis, pyruvic acid, is no longer entering the mitochondria, but is being diverted to lactic acid, a waste product of the glycolytic pathway. And that acidifies the cancer microenvironment, so cancer then becomes a disease of cells that proliferate with instead of producing oxygen, CO2, and water, they’re producing lactic acid as a waste product. Warburg noticed that all the major cancers that he studied were all blowing out large amounts of this lactic acid. And he said that-
Dr. Mark Hyman: Which is what accumulates in your muscles when you over-exercise that causes soreness.
Dr. Thomas Seyfried: Exactly. Exactly. Then that deficit is made up as soon as the muscles can be oxygenated. They go back to respiring. The muscles have a capacity that when oxygen becomes deficient from overuse of muscles, the muscle will then use the local glucose to produce massive amounts of quick energy with the waste product of lactic acid, which goes back into the bloodstream in exercised folks. And the lactic acid goes to the liver and is created back to glucose. That’s the core recycle. And Carl and Gerty Cori received the Nobel Prize for their recognition of how lactic acid from muscles can be reconverted back into glucose for the body.
Dr. Mark Hyman: Okay, hold on one sec. Hold on one second. I think that what you just said was so important, I want to make sure everybody gets it, and then we can continue with on how this relates to cancer. Everybody basically, from my understanding, is that when we eat, our food is primarily turned into glucose. Glucose then has to go through this process of breakdown into byproducts we call pyruvates. And there’s a whole bunch of steps that then turns that into energy in the body. With cancer cells, that basically process is kind of defective. Instead of turning into easy form energy from glucose, it creates lactic acid, which changes the whole environment itself.
Basically the other point I think it’s important people realize is that your body is like a hybrid car. It can run on gas or electric. Your cancer cells … And the gas is sugar and the electric is fat. In cancer cells, they don’t run well on fat, and it basically starves them. They only can run on sugar, which is gas. But it’s kind of the dirty burning fuel. And that ends up with all this linkage of cancer to things like diabetes and insulin resistance and all these various factors. That’s all how it ties together.
Now, take us down sort this process of the secondary pathway, which is fermentation instead of what we call the primary pathway of burning energy, which is oxidative phosphorylation, essentially Krebs cycle. It’s how we break down sugar and energy. I think I just sort of want to reinforce that, ’cause there was a lot in there.
Dr. Thomas Seyfried: No, no, you’re 100% correct, Mark. This sometimes can be a little overwhelming.
Dr. Mark Hyman: I mean, even most doctors, by the way, we remember biochemistry for just enough for our exams, and then we forget it all, including the Krebs cycle, which is what you’re talking about, which is how we turn food and oxygen into energy. But it’s one of the most important things we do in [inaudible 00:20:25].
Dr. Thomas Seyfried: No, it’s a really interesting thing because most of us, when we had to study the Krebs cycle as a requirement, only because it was torturous to try to memorize all the stuff. And it was no pleasure in doing that other than the fact that you say, “Oh, if you memorize it, you regurgitate it on a test, and then you wouldn’t have to worry about it again.”
Dr. Mark Hyman: That’s right.
Dr. Thomas Seyfried: But we are in a different sphere now, where we really need to understand that in order to manage a very devastating disease. I took a completely different view of these torturous biochemical pathways when I said I needed to know this in order to manage the cancer, in order to have an effective non-toxic management of the tumor. Now it becomes a process. It becomes part of your soul to understand these processes, because you’re going to be able to wield the power of your knowledge to manage a disease, because you finally understand what all this crap meant.
Dr. Mark Hyman: That’s right.
Dr. Thomas Seyfried: Now we realize that, as Warburg said, cancer cells don’t need oxygen for their growth. He showed data that he can take all the oxygen out of the system, and these tumor cells were still growing fine. His argument was they replaced their oxidative phosphorylation or energy through respiration with energy through fermentation. Fermentation is energy without oxygen. And he said that they were getting [inaudible 00:22:06]-
Dr. Mark Hyman: That’s how you make wine or beer, right?
Dr. Thomas Seyfried: Yeah. Well, the byproduct, that’s alcoholic fermentation. Lactic acid fermentation. There’s an extra step that the yeast use to convert the lactate into ethanol, but that’s another step. Our muscles and our cancer cells are producing lactic acid as a waste product of the fermentation process as a result. But what Warburg was saying that you have to replace energy. Without energy, nothing will grow, period. That’s the key basis of all of our life existence. Without energy, we die real quick. And you want to know how fast we can die? If people drink cyanide, you die real, real fast. As I said, that used to be-
Dr. Mark Hyman: It poisons the mitochondria.
Dr. Thomas Seyfried: Yeah. It poisons complex four, and the mitochondria shuts down electron transport, prevents oxygen from binding to electrons, and your whole body just shuts down instantly. So cancer cells don’t-
Dr. Mark Hyman: In other words, you can’t make energy if you drink cyanide, you just can’t make energy, and then you die.
Dr. Thomas Seyfried: No, you can’t make energy. Your brain dies. Your heart dies. Everything dies. Anything that’s linked to oxidative phosphorylation dies real quick, except a cancer cell. So Warburg said, “Cancer cells are resistant to cyanide.” I said, “Whoa, so they don’t need oxygen.” And they don’t. They can live in cyanide. And I said, “Whoa, what the hell is this?” But he said a long time ago, in the 1920s, they were showing this kind of thing. They would take a rat that had a tumor, and they would inject the rat with cyanide, and the rat would die instantly, but not the tumor. You could take the tumor out and grow the cells and culture was fine. The tumor was resistant to the cyanide. And he said, “That’s because they’re oxidative phosphorylation. They have replaced oxidative phosphorylation with fermentation, which is energy without oxygen.” That became very clear from his hundreds and hundreds of scientific papers and analyses.
I went back and I looked at all that stuff really, really carefully, and confirmed in no uncertain terms that Otto Warburg was 100% correct in his knowledge of the origin of cancer. He was not correct in the readouts, and I’ll explain that in a minute because we’ve cleared that all up, the misinformation regarding the readouts of dysfunctional respiration. But he claimed that cancer starts with a chronic disruption of energy through oxidative respiration. Then the cell will gradually over time transition to this ancient process of fermentation. He also clearly said that if you damage respiration too acutely, the cell will die, and you will not get a cancer cell from a dead cell. And that’s exactly what happens with the cyanide. If the whole body is dead, there’s no way you’re going to get a cancer cell. But if you have a cancer cell in there, it’s not going to die from cyanide. So as I said, people with cancer drink cyanide to kill themselves, well, they’ll kill their body, but the tumor cells in their body will still remain alive, as long as they have the fermentable fuels in the microenvironment.
At that time, Warburg figured that the major fermentable fuel was the sugar glucose. Glucose can either be completely respired in the mitochondria of the cell, or it can be fermented if the mitochondria are not functional, or the individual would be in a low oxygen environment. It became clear to Warburg that the release of large amounts of lactic acid from tumor cells was the result of a defect in oxidative phosphorylation. This then could explain the origin of cancer.
Problem is in the 1950s, Sidney Wienhouse and others, who was the head of the National Cancer Institute, and rightly so, reported that there were some cancer cells that took in as much oxygen as some normal cells. So he said, “Warburg must be wrong, because we’re seeing cancer cells that are taking in oxygen as avidly as normal cells, and yet the cancer cell is still blowing out lactic acid. What’s going on with this?” So they said then, “Oh, the cancer cell needs so much energy, it both respires and produces lactic acid at the same time.”
This major controversy and battle went on for years, and is still going on for many people today in the papers that they publish showing that cancer cells consume oxygen just as readily as normal cells in culture, and therefore cancer cells are using oxidative phosphorylation. Wrong. We’ve shown that’s not the case. It turns out that the tumor cells do in fact consume oxygen, but they’re not using it for ATP synthesis. They’re not using the consumed oxygen for generating energy through oxidative phosphorylation. They are using it to produce reactive oxygen species, ROS. ROS are carcinogenic and mutagenic. These oxygen radicals damage DNA, RNA, and proteins. They cause the mutations that you see in the nucleus of the tumor cells. The oxygen consumed by cancer cells is producing DNA damage as a downstream epiphenomenon of the damage to oxidative phosphorylation.
The cancer field today is focusing on mutations and targeting mutations. These are all effects. They’re not the cause of cancer. And this goes back to the argument with Sydney Wienhouse and Warburg in the 1950s, except the folks today absolutely do not understand, do not appreciate, or cannot accept the fact that the oxygen consumption in cancer cell is not used for oxidative phosphorylation. It’s used for reactive oxygen species and other reactions not involving ATP. You have to put the story together.
When you mentioned CAR-T immunotherapy, all these immunotherapies, they’re based on the somatic mutation theory. Warburg was the initiator of the mitochondrial metabolic theory of cancer. I will explain more, because he did not know about glutamine fermentation, which we now know about. He also assumed that the oxygen consumed by cancer cells, even though it was low, was still linked to oxphos. Okay, that’s a misunderstanding on Warburg’s part.
Dr. Mark Hyman: You got to give him credit. That was over 100 years ago.
Dr. Thomas Seyfried: It was 100 years ago. And because the pathway for glutamine fermentation was not yet developed, so he did not know about the second major fermentable fuel. He was absolutely right on the origin of cancer. He was incorrect on assuming that lactic acid production equaled a certain amount of ATP. We now know that that calculation is somewhat in error. We also know that oxygen consumption is in error, so we can put it all together. Warburg was 100% correct in the knowledge of how cancer started. His readouts were incorrect, and we’re polishing it all up. So the mitochondrial metabolic-
Dr. Mark Hyman: [inaudible 00:29:50], let me take a pause there for a sec.
Dr. Thomas Seyfried: Yeah.
Dr. Mark Hyman: Basically what you’re saying is that most oncology today is focused on the idea that cancer results from genetic mutations in the cancer. However, what we’re now learning at the same time is that you can take a hundred cases of breast cancer, and they may be all genetically very different, or colon cancer or prostate cancer or pancreatic cancer. And so even though they have the same name, the same pathology under a microscope, the underlying genetics are quite different. We’re playing a little bit of whack-a-mole. Now, there may be some ways of improving cancer response to chemotherapy by identifying which genetic mutations there are, and which drugs work better for which ones. It’s sort of a incremental improvement, but it’s not a cataclysmic shift in our thinking around cancer, which is moving from a genetic theory to a metabolic theory.
I think the metabolic theory is quite interesting. I think it clearly needs to be fleshed out more, but it looks like it’s holding promise to deal with things like stage four melanoma, stage four pancreatic cancer, stage four breast cancer. Cancers that are really death sentences are responding, even glioblastoma, which is brain cancer, very well to ketogenic diets. You have to be able to sort of navigate this new landscape where certain cancers are really responding to a metabolic approach, and so we can’t just sort of relegate it to some crazy whackjob theory. This is actually now becoming more mainstream thinking.
Dr. Thomas Seyfried: Well, going back to what you said about the breast cancer, when you look at individual breast tumors, they have different stage, one, four, all the different kinds of HER-2 and …
Dr. Mark Hyman: Yeah, the staging and the typing, which actually may be less important.
Dr. Thomas Seyfried: Yeah. But you’re 100% correct. When you look at the genetic profiles of all these different tumors, they’re all essentially different from each other. I mean, there’s some commonalities in mutations of course, but many studies have shown if we take all the individual cells, many individual cells out of a tumor and do a full genomic sequence, no two cells in the tumor exact have the exact same kinds of mutations. Yet every cell in that breast tumor has dependency on fermentation as a source of energy. All the cells have one major common problem or phenotype or observation. They’re all fermenting, regardless of what their mutations are. The common pathological phenotype is fermentation.
Then the simple question is, how do they get their energy from fermentation? And the two fuels that drive fermentation are glucose, the sugar, and what we have shown is the amino acid glutamine. Now, glutamine for the cancer field, people will say, “Oh, we all knew glutamine was a big, big role in cancer.” You guys in the field thought it was being respired. No, because the oxygen … No, it’s not respired. It’s fermented, just like the glucose. But it’s also fermented in the mitochondria. The mitochondria, the pathway is called glutaminolysis, and it’s a fermentation pathway in the mitochondria. You have a fermentation pathway in the cytoplasm and you have a fermentation pathway in the mitochondria, which makes it look like the mitochondria are respiring, especially when they’re taken in oxygen.
We had to parse out all this stuff and clearly define what the actual biomedical biochemical mechanisms are that are driving the beast. And the beast is driven by fermentation. And you’re right, Mark. The cells in the glioblastoma, the cells in colon, lung, they’re all fermentors. That’s why when you take CAR-T immunotherapy, if you’re not hitting the fermentation pathway, you’re essentially missing the target. Nothing could be like when you say, “Oh, we have targeted therapies, precision medicine.” These guys, these targets … I mean, they’re missing the target. And you pay a lot of money for a missed target. And then you say, “We’re going to use precision medicine.” “Yeah, well if it’s so precise, how come you blew out my liver when you were trying to cure my lung cancer?” [inaudible 00:34:13].
Dr. Mark Hyman: Exactly. I think the problem, most of the treatments we have now are really toxic. Radiation, chemotherapy, surgery is a bit crude. And what’s amazing about metabolic oncology is the therapy is diet, and maybe some other compounds that block some of these fermentation pathways, that really have not only no side effects, but have a ton of beneficial effects in terms of overall metabolic health, in terms of reducing inflammation, improving stem cell function, causing DNA repair, and helping deal with oxidative stress. I mean, the list goes on about how this works. It’s quite amazing.
Dr. Thomas Seyfried: No, it is. It’s remarkable. And because we’re going back to the origin of many of the diseases that we have, and a lot of this is systemic inflammation, chronic exposure to different chemicals. You put all that together and you end up with diabetes, cardiovascular disease, cancer, dementia, you end up with all these kinds of chronic diseases. And a lot of it has to do with disturbed energy. Metabolic homeostasis is disturbed in many of these chronic diseases. The issue for us, though, is ferreting out the mechanisms of how cells grow. Cancer cells grow in a dysregulated way. I don’t want to become too diffuse and say, “Okay, let me jump now into Alzheimer’s and show you how this works. Let me jump into type two diabetes and show you how that works.” The major focus we have right now is correcting massive misinformation on how the cancer cells express this dysregulated growth, because ultimately that’s what the disease is. It’s cell division out of control. These cells are dividing out of control because they have lost their ability to use energy through respiration, have fallen back on ancient fermentation pathways. The organelle inside the cell that controls the cell cycle and regulated growth is the mitochondria.
Warburg clearly showed many years ago, and I have in my own work validated everything that Warburg said with respect to mitochondrial dysfunction, that the organelle controlling the differentiated state and regulated growth is dysfunctional, and therefore the cells are falling back on ancient fermentation pathways and are dysregulated in their cell growth. What’s the best way to manage cancer is pull the plug on their fermentation fuels. And there’s only two fuels that can drive this beast, and it’s glucose and glutamine. And then they can’t, as you mentioned earlier, they can’t burn fats or ketone bodies, because you need a good mitochondria, oxidative phosphorylation system to generate energy from fats and ketone bodies. The fats and ketone bodies, though, help the heart, help the brain, especially for ketone bodies.
You mentioned, as you said, all of these different chronic diseases can be improved significantly by this metabolic approach, because when you burn ketones, you essentially increase the metabolic homeostasis of normal cells, and the cancer cell is marginalized. It can’t use the ketone body or the fat. You really put them in a very compromised position, and they will gradually be eliminated.
And not only that, in our paper, in my book, and in the paper we just showed for managing cancer in the dog using purely metabolic therapy, when you cut the calories down, we have this process called autolytic cannibalism. It’s very interesting. All cells in the body must carry their weight when food restriction. There has to be a coordinated interaction among all the cells in our body. And when you have a cancer, a group of cells that are using energy in a very inefficient way and not contributing to the society of the cells, the body will turn on those cancer cells and use them as fuel, eat them, and supply their metabolites for the rest, called autolytic cannibalism. And in order to get to get into that stage, you have to lower blood sugars and you have to increase ketones, and then the body starts turning on these cancer cells and dissolving them.
Dr. Mark Hyman: So does it have to be both calorie restricted and ketogenic? Because ketogenic diets aren’t necessarily calorie restricted, although people might want to eat less because they’re not as hungry because fat inhibits appetite.
Dr. Thomas Seyfried: In humans, the ketogenic diet, high fat diet impacts the hormone cholecystokinin, which shuts down appetites. It impacts on the 10th cranial nerve.
Dr. Mark Hyman: Well, you don’t have to deliberately restrict calories for the ketogenic diet to get cancer [inaudible 00:39:09]?
Dr. Thomas Seyfried: Well, most people do because their appetite is turned off. It’s a indirect calorie restriction. Nobody sits down and eats a whole pound of butter. Nobody’s going to do that. As a matter of fact, we are learning now from a lot of our colleagues, there are many palatable types of ketogenic diets. We developed the glucose ketone index calculator to allow the cancer … I did it mostly for cancer patients, but it seems like people just want to get healthy, they use the GKI. It’s the ratio of blood sugar to blood ketones using a finger prick. You use Keto Mojos or these different instruments to measure this. Regardless of what you’re eating, if you can keep your GKI levels to 2.0 or below, I mean, you’re going to put significant metabolic pressure on these tumor cells.
So people say, “Oh, the ketogenic diet is unpalatable.” Well, you can develop a Mediterranean diet that will do the same thing. Just got to use the GKI to let you know what you can eat and what you can’t eat. And people are learning now, “Hey, I’m a vegan. I can get my GKI down, and I feel pretty good about the whole thing.” And this other guy, “I’m a carnivore, and I can do the same thing,” and the pescatarian and whoever the hell else you want to be.
The bottom line is, if you have an instrument now and a ratio to put pressure on your cancer cell, and you can build your own diets to see for this. That’s a nice tool that allows the physician or the patient to know when they’re in this zone. And then when they’re in this zone of low glucose ketone index, that’s when you bring in the drugs like glutamine inhibitors and other glucose inhibitors to fully target and eliminate these tumor cells in a non-toxic way. It’s a strategy. You have to be aware of how to do this. You just can’t all of a sudden go into a clinic at the top medical school and say, “Man, I’d like to have metabolic therapy instead of CAR-T immunotherapy.” “Oh, we don’t know how to do this. This doesn’t work. There’s no evidence.” Well, you got to read those scientific literature.
Dr. Mark Hyman: My favorite thing is that, “There’s no evidence.” It translates as, “I haven’t read the evidence or looked for the evidence.”
Dr. Thomas Seyfried: This is another thing. Sometimes I do these podcasts and people say, “Oh, who’s this guy pulling this crap out of his ass, saying and all this kind of stuff?” And I said, “Well, why don’t you read my papers?” I mean, it’s open access, it’s not like I’m making this stuff up. We’ve been spending 25 years doing the research, and we published the research. It just so happens you don’t read the research. I mean, what am I supposed to say?
Dr. Mark Hyman: [inaudible 00:41:48].
Dr. Thomas Seyfried: So everybody goes, “Oh, where’s this guy getting all this information he’s saying?” No, I did the damn experiments for Christ’s sake. I know what I’m talking about. And then I published them. “Oh, I wasn’t aware of that.” “Well, what more you want me to do? Write it in crayon and put a big sign on the side of the road.”
Dr. Mark Hyman: There’s only about nine million papers in national library medicine. I think most doctors haven’t read a fraction of that.
Dr. Thomas Seyfried: No, and it’s true. And I don’t blame them. They’re overwhelmed with their cancer patients, and trying to do the best they can. But what bothers me is the absolute resistance on the part of the medical establishment to might even consider what we’re saying. And as a matter of fact, as I said, you only have two major theories to describe the origin of cancer. That is the somatic mutation theory, which is advocated by the National Cancer Institute. If you go to the National Cancer Institute, the thing you say about cancer, “Cancer is a genetic disease.” This drives the grant support from the National Cancer Society and the NIH are all supporting gene approaches, which then involves the immunotherapies and all this crazy stuff that you hear on television every night. It’s all driven by the somatic mutation theory of cancer.
The alternative and the correct theory is that cancer is a mitochondrial metabolic disease. So it’s the mitochondrial metabolic theory. When patients go into the clinic, they should ask their oncologist, “Is the treatment you’re giving me based on the somatic mutation theory, or on the mitochondrial metabolic theory?” Of course, it’s like a deer looking into the headlights. Most of them just don’t know anything about what I just said. But the tragic thing is that the National Cancer Institute itself is pushing misinformation on this incorrect theory. We’ve presented so much evidence that the only way you can say cancer is a genetic disease is through ideological dogma. It can no longer be rational thinking. It’s ideological dogma is maintaining the status quo in managing cancer. And dogma is an extremely powerful force on the brain. It underlies religion, it underlies political affiliations, and it also underlies the somatic mutation theory of cancer. When you put all that together, you can see why we’re not making the kind of advances that we should be making. It’s due mostly to a dogmatic view that cancer is something other than what it actually is.
Dr. Mark Hyman: Talk a little bit more about the glutamine, because it seems like we can restrict sugar pretty easily through a ketogenic diet, and reduce our carbohydrate intake and switch to mostly fat. And also, we have to limit protein, because protein can turn into sugar in the bodies, be careful it’s not a high protein diet. But what about glutamine? Because glutamine is an essential amino acid. It’s involved in [inaudible 00:44:56] production. It’s found in many healthful foods such as fish and dark green leafy vegetables, which we think we should eat. Eggs, nuts and seeds, soybean, seaweed, meat. Wow, what are we going to do? How are we going to get away with limiting glutamine?
Dr. Thomas Seyfried: This is so, so important, because I don’t know what it is. People from all the other podcasts that I’ve done, they all rush out and say, “Well, what can I eat to reduce glutamine?” Nothing. You can’t. There’s no diet that can reduce glutamine. Now what we did find, the work done by George Cahill and others, prolonged water-only fasting will reduce glutamine. But glutamine, as you said, is a non-essential amino acid because we can make it predominantly from glucose, actually. But there’s no diet by itself that can reduce glutamine. Therefore, we need drugs to target the glutamine. I want to say it again. There is no diet that can effectively reduce the availability of glutamine in our body. That’s why we need drugs. And the drugs are designed to further put the pressure on glutamine.
As you said, this is an incredible amino acid. It may not be considered an essential amino acid, but it is essential for the immune system, for our gut, and for the urea cycle. That’s why the glutamine issue allowed me and my colleagues to develop the press pulse strategy for managing cancer. You can press glucose, as you said, Mark. We don’t need glucose. We can replace glucose with fats and ketone bodies that the tumor cells can’t use for energy. We can push glucose levels down pretty low. And then the rest of the normal cells, when they’re deprived of glucose, will compete directly with the tumor cells for any of available glucose in the body. We got the glucose thing under control.
The glutamine issue now requires kid gloves, because we know how important that molecule is for the normal physiological health of our body. When I say press pulse, we press glucose chronically stress, just diet and some small amounts of other drugs can press glucose without harming the body. But we pulse glutamine. We can’t chronically deprive our bodies of glutamine, because it’s an essential amino acid. We put a drug like 6-diaze-norleucine, which is DON, which has been a known glutamine inhibitor. It shuts down the glutaminolysis pathway, so you can’t metabolize glutamine to glutamate.
But we can’t be too aggressive with that, because if we’re too aggressive with it, we’re going to damage our immune system, we’re going to damage our gut. We can damage things. We just put it in there for a short period of time at a particular dosage, slaughter a whole bunch of tumor cells, and then pull it away. And then we need our immune cells to come in and pick up the corpses. Our immune cells, our immune system and the tumor are both utilizers of glutamine. So yeah, you can kill tumor cells because they’re absolutely dependent on glutamine. But we can also paralyze the function of our normal immune system if we keep glutamine targeting too aggressive on there. We have to pull it back, allow our indolent immune system to become aggressive again, pick up the dead corpses of the cells that we just killed, and then hit them again with a small dose of glutamine.
You press the glucose, hold that down with diet, and then you pulse the glutamine. Eventually you gradually degrade the tumor while enhancing, at the same time, enhancing the health and vitality of all of the normal cells in the body, including the immune system. You have to know biology, you have to understand the biology of the different systems that you’re working with, because you can play off one biological system off of another. It’s a beautiful, elegant system. Well, once people understand how to do this, it’s going to be the new paradigm shift. It’s going to be the way we’re going to manage all these diseases.
Dr. Mark Hyman: You have to do both, right? You have to do both the glucose restriction and you have to inhibit glutamine pathways to a drug or a compound, which is not actually an approved drug. It’s some research compound right now, which is not available.
Dr. Thomas Seyfried: Well, it was approved. I mean, they did a phase two trials with this drug. I mean, it was used in little kids with leukemia. It’s just that they never targeted the glucose when they used it, and they didn’t know the dosages. So it’s like anything. If you don’t know how to use the tool, it’s never going to give you the outcome that you would’ve expected.
Dr. Mark Hyman: Does it have side effects?
Dr. Thomas Seyfried: Well, what we showed, yes, of course it has side … Like any drug. I mean, radiation has side effects, CAR-T, all this stuff has side effects. But what we showed is that when you administer DON with the ketogenic diet, you use much lower dosages and you pulse the system, you don’t press the system. Therefore you eliminate the toxicity while at the same time improving therapeutic efficacy. Therefore you learned how to use the tool. If you don’t use the tool … That’s what they said. “Oh, we can’t use DON because it was too toxic.” Well, you didn’t know how to use it. You got to use it. You got to know how to use this drug. And believe me-
Dr. Mark Hyman: Have there been clinical trials in humans on this?
Dr. Thomas Seyfried: Of course they’re doing it now at Johns Hopkins. They took that drug, DON, and they put a little tail on it, made it like a new drug. There’s two ways to make a new drug. One, you can take an already existing drug, modify it slightly, and then say, “Oh, we’re going to make a billion dollars on this.” The other way to do it is like we did. We have a drug that we knew worked, but we didn’t know how to use it in the correct context. We changed the context, and the drug now becomes super powerful. So it’s like a new drug, but you put it into a different environment, you get the same effect. My goal is to save lives and improve quality of life. Other people may want to make billions of dollars on this stuff. But either way, the bottom line is that if you use the drug from Johns Hopkins or you use the regular drug in a different context in a different way, the outcome is going to be similar.
But now the problem of course, is if you use DON by itself, you’re never going to get the complete therapeutic benefit unless you target the glucose. You got to target the glucose with it. And we also found that in administration of DON to brain cancer in a ketogenic diet, the ketogenic diet facilitates delivery of the drug through the blood-brain barrier onto the target. Clearly you’re going to get much more bang for your buck by administering the drug in a ketogenic diet than if you administered in a high carbohydrate diet. We published beautiful papers, beautiful papers on this.
Dr. Mark Hyman: Now what about the data around the Inuit? Because they were populations that lived in the Arctic Circle who ate primarily fat, whale blubber, seal. They essentially were on ketogenic diets, and they had very few cancers, right? I mean, what did we learn from those populations?
Dr. Thomas Seyfried: Well, we have a book coming out from Tim Nokes’ group, a big book on ketogenic diets used for everything. And they talked about the Inuits in that book. When they were first evaluated, they were considered to be resistant to cancer and some of the other chronic diseases. And they never ate … They ate very little vegetables. Of course, seasonal, everything had to be be seasonal. But yeah, they were in nutritional ketosis probably for the majority of their lives. And they didn’t have any cancer. I visited the medical hospital-
Dr. Mark Hyman: Is that because we just didn’t diagnose it, or ’cause they actually didn’t have it?
Dr. Thomas Seyfried: Well, it’s a combination of both, probably. I mean, who would know whether some guy might have had some problem? I mean, there wasn’t a lot of medical evaluations. But the Western physicians, I think mostly from England, I have to go back and double check on that. But they did some evaluations. I mean, just overall chronic, any kind of chronic diseases. The bottom line was cancer was not recognized as being any concern in these folks. But when I visited the medical school at Thunder Bay, Canada, I gave a lecture there. That medical school predominantly focuses on the health of Inuits, because a large population of Inuits are in the Canadian provinces, in the northern Arctic circle. These folks were just decimated by type two diabetes, cancer, dementia, all kinds of things that they never had were afflicted with until Western diets and lifestyles came into their environment.
The Inuits are just one example. The other example is Albert Schweitzer’s evaluation of the African tribes in various countries of Africa, and the African tribes that lived according traditional ways. He actually was looking for cancer, and he looked at almost 40,000 Africans and found not one single case of cancer in tribes that were following traditional ways. So clearly cancer is a disease of Western diets and lifestyles. And because it never existed, nor does it exist in our closest primate relatives, the chimpanzee, which is about 98.5 percent similar to us in gene and protein sequence. These animals are under constant veterinary surveillance at the major zoos, and there’s never been a documented case of breast cancer in a female chimpanzee despite the fact that they have very similar, if not identical genes and proteins that we have.
What is it about a chimpanzee, or Inuit or African tribes living according to traditional ways, that makes cancer an extremely rare event in their environment? Clearly it’s the environment that we live in that’s putting us at risk for all these chronic diseases, including cancer. We know how it arises. We know that you cannot get cancer if you maintain healthy mitochondria. So it starts, as Warburg said, with mitochondrial disruption. So then the question is, “Well, how do I prevent cancer?” Well, if you can keep your mitochondria healthy. Well, how do you keep your mitochondria healthy? Avoid highly processed carbohydrate foods, do exercise, this kind of thing. In other words, now that we know the plan, who is willing to adopt the plan to their lifestyle? And it’s hard, because every corner we have fast food. And we can’t do the kind of experiment that would show the evidence if we took chimpanzees and gave them an American diet and lifestyle in the zoo. Jelly donuts, pizzas, big gyro sandwiches.
Dr. Mark Hyman: Sometimes they get-
Dr. Thomas Seyfried: I asked the zookeeper at the San Diego Zoo. I said, “How would these bonobos …” They have some bonobo. “Oh, they would eat those donuts like there’d be no tomorrow.” But I said, “Why don’t you go down to the Dunkin’ Donuts and bring them in a box of jelly fills?” They said, “Animal cruelty.”
Dr. Mark Hyman: That’s right. That’s [inaudible 00:56:33].
Dr. Thomas Seyfried: So I said, “what about us?”
Dr. Mark Hyman: That’s so funny.
Dr. Thomas Seyfried: I’ve always asked that to the veterinarians at the zoos with their primate. I said, “Why don’t you guys go down and get … You think this guy would love a big pizza margarita?” “Oh, they’d be all over it.” But they can’t do that, because it would be a cruel thing to do to them. And I say, “Well, we’re doing it to ourselves, and now we’re suffering from all the consequences of this action.” And consequently we have all these chronic diseases. We can manage them all very effectively. If you listen to the TV coming out with all these wonderful ways, “Take this drug, that drug, do this, and then you got a thousand side effects that’ll kill you before the disease will.” It’s really crazy, man. I don’t know what to say.
Dr. Mark Hyman: I want to ask you about a couple more things that I think are interesting in your work. One is the use of hyperbaric oxygen therapy as an adjunct to what you’re talking about, in combination with interrupting the glucose pathways and the glutamine pathways. And by the way, just so everybody knows, the way we detect cancer in screening for recurrence or looking at someone’s overall status is we use a PET scan, which is basically a special type of scan where we give people a radioactively labeled sugar, basically sugar, radioactive sugar. And it goes back to the cancer. And that’s how we tell what the cancer is. It doesn’t work for the glutamine pathways, but it actually is how we detect metastatic cancer.
It’s weird. The doctors say to patients, “Oh, don’t worry about what you eat. Why don’t you eat ice cream and milkshakes?” And I’m like, “What are you doing? This doesn’t make any sense.” Especially in the context of knowing just from pure well-established research that insulin resistance and pre-diabetes and the whole phenomena of too much sugar in our diet is driving so many cancers. The major cancers, colon, breast, prostate, even some lung cancers, pancreatic cancers are driven by sugar.
Dr. Thomas Seyfried: Yeah. And you’re right about that. I mean, we use fluorodeoxy glucose. It’s an analog of glucose that can’t be metabolized, so it collects in the tissue and it lights up, and you say, “Oh, there’s your cancer right there. It’s sucking down the glucose.” And then on the same breath, you’re going to have a, “Drink Infamel to help you.” And then to one of the …
Dr. Mark Hyman: You mean Ensure. Ensure and Boost, and …
Dr. Thomas Seyfried: Yeah, Ensure.
Dr. Mark Hyman: Pure sugar, right?
Dr. Thomas Seyfried: Yeah. And then you take a guy, and they’re so fearful of weight loss in a cancer patient. You take a guy who weighs 350 pounds and you say, “Now you got to eat, keep your weight up. We wouldn’t want you to lose any weight.” I mean, you got to be nuts to say something like that. But the whole thing here is getting back to hyperbaric oxygen, which was your original question. Dom D’Agostino and I … Dom is a guy who’s constantly in nutritional ketosis. He had done some studies in his lab showing that in hyperbaric pressure, the cancer cells were exploding, and they would create a tremendous amount of reactive oxygen species. Furthermore, from not only the fact that they produce ROS, but the oxygen under pressure enhances the killing effect of the ROS.
What we did in our press pulse big paper that we wrote, the press pulse strategy for managing cancer, hyperbaric oxygen was part of the pulse strategy. If the patient can get into therapeutic ketosis with a glucose ketone index of 2.0 or below, we would then 2.5 atmospheres for about 90 minutes. You could put that patient in hyperbaric oxygen, and hyperbaric oxygen would essentially facilitate the killing of the tumor cell through oxidative stress. It’s important to remember that radiation and some of the toxic drugs that we use for cancer management in the clinic also kill cancer cells through oxidative stress. But the key is with hyperbaric oxygen, you’re killing the cancer cell with oxidative stress without causing collateral toxicity to the rest of the body.
It beautifully dovetails in with the overall concept of metabolic therapy, and that becomes another arm of treatment is hyperbaric oxygen once the patient is in therapeutic ketosis, because we know that that’s when hyperbaric oxygen will have its greatest therapeutic benefit is when that patient has the glucose ketone index value, which could change during the course of the day. He or she would know when to go into the chamber for oxygen therapy when their GKI would be at the lowest point during the day, and then they would schedule treatments that would be based around those values. So clearly it becomes an arm of the therapeutic strategy called mitochondrial metabolic therapy, is the whole concept for this new treatment strategy.
Dr. Mark Hyman: Yep. So Hyperbaric oxygen, ketogenic diet. Let’s talk about fetal butyrate and glutamine, because this is a compound that’s been around for a long time, and it seems to bind to glutamate and it causes excretion of the urine. Is that a reasonable approach, and is that available as a drug still?
Dr. Thomas Seyfried: Yes, it is.
Dr. Mark Hyman: What do you think about that?
Dr. Thomas Seyfried: Well, I think for blood cancers it could be very effective. I haven’t tested it yet, because we do most of our work in the mouse. And the way it works in humans is phenyl butyrate is metabolized to phenyl acetate, and phenyl acetate then binds with glutamine and you kind of flush it out of your body. The mouse doesn’t have that enzyme, so we’re never able to test phenyl butyrate in a full effective way in the preclinical system. But I certainly think it could be effective for … Because glutamine is the most abundant amino acid in our blood, in the blood of a normal person. It’s about five milligram. Five millimolar, I guess it’s about five millimolar concerts. It’s the most abundant amino acid, because it plays such a vital role in so many of our physiological processes.
But phenyl butyrate could be an effective way to reduce levels, especially under calorie restriction and ketogenic diets, could be further a very powerful way to kill blood cancers. And blood cancers, like brain cancer, colon cancer, they all have damaged oxidative phosphorylation. They’re all fermenting. They’re using glucose and glutamine, and they would be even more vulnerable to … I think. I don’t want to say that with any level of certainty until I actually do the experiments myself. Most of the knowledge that I provide or tell is because I’ve done the experiments and I’ve looked at different things. But I think for humans, it could be a real value to try to reduce, especially for blood cancers. Whether it works for solid tumors, it’s hard to say, because the microenvironment of the solid tumor may not be permeable to phenyl butyrate or phenyl acetate. Therefore, I cannot speak to that.
Dr. Mark Hyman: A lot of your work has been done in animal models, in lab data. Can you talk about some of the clinical human trials that are happening now, or the ones that have been done? What have we learned, and where is this being effective? I’ve seen some pretty remarkable things happening in glioblastoma and other cancers. Can you talk about what we know right now in humans, and where do you think we’re going to be in three, five, ten years with cancer treatment?
Dr. Thomas Seyfried: Well, we’re developing a treatment protocol right now as we speak, a comprehensive treatment protocol for humans so that we bring together all of the things that I was saying in a how-to manual and strategy. Once the medical professionals read this, they’ll know what to do and how to do it. I am working with folks in different countries right now where there’s a little bit more flexibility in what we’re able to do. And to be honest with you, Mark, I’ll tell you the mouse basal metabolic rate is seven to eight times faster than that of a human, so everything happens in kind of a split second timeframe. Whereas in humans, we have so much more flexibility to really max out these therapies.
And what we’re seeing in humans, we’re seeing therapeutic benefits in humans that we never could see in the mouse. We have not cured any mice with advanced metastatic cancer. We’ve managed it, certainly, massively better than if we didn’t do the right things. But in humans, we’re seeing much, much greater therapeutic benefit. And dogs, too. I want to emphasize that cancer is the number one killer of domestic dogs, and we’re starting to see tremendous therapeutic benefit in dogs because their basal metabolic rate is closer to that of a human than it is of a mouse.
Dr. Mark Hyman: It’s interesting, I had a lab with widespread metastatic lymphoma who was given a few weeks to live, and I basically put him on a ketogenic diet, and he lived for at least a year when he stopped eating the food. And then I said, “All right, I’ll just give him the food he likes again.” And then he died within a few weeks. It was quite amazing.
Dr. Thomas Seyfried: Yeah, no, it’s unbelievable. As a matter of fact, we published the papers, Open Access in Frontiers and Nutrition, on the complete resolution of mass cell cancer in a dog with no radiation, chemo, steroids, or any of this. Just metabolic therapy. We published the recipe in there. If anyone has a dog with cancer, the recipe for managing the cancer without toxicity is present in that paper. It works in dogs really well, and I think we’re going to be able to manage the cancer in the dogs. The dogs become now a really good tool to test out all these things that we want to plan to put into humans.
But what I do in my preclinical mouse models is we can troubleshoot all the different strategies, doses, timing, and scheduling that will be necessary for the eventual long-term management and possible resolution of the majority of human cancers. The funding for our research comes predominantly from private foundations and philanthropy, because there are folks out there that know we are on the right track. And as you said, when will this become a reality is not clear to me, because you have powerful institutions that have built up around the somatic mutation theory of cancer, so you get this dogmatic ideology that keeps the status quo, but you have to break that down.
Dr. Mark Hyman: Yeah. Basically the Earth is flat, and you’re [inaudible 01:07:15] the Earth is round.
Dr. Thomas Seyfried: Well, the center of the solar system is the Earth, not the sun.
Dr. Mark Hyman: That makes sense.
Dr. Thomas Seyfried: This was the heliocentric, geocentric theory that was broken down. And the Catholic church adhered very strongly to keeping the earth in the center of the solar system until Galileo, Copernicus, and Kepler came along to prove that it could not be. We have absolutely shown that cancer cannot be a genetic disease, absolutely cannot be a genetic disease. I have written all these papers and people say, “Oh, I don’t believe you. I don’t believe you.” Well, read the damn papers, will you? And then you’ll come to the realization that this is what it is.
Once you realize it’s not a genetic disease and it is a mitochondrial metabolic disease, the field will shift over. And it will shift over because people want to live. I mean, you have a very anxious population of suffering, people that would like to have their disease managed in a more logical way, not through some medieval kind of stuff that we’re doing to these folks today. Clearly it’s going to happen. It has to happen, and it will happen, because what we’re doing today is not working. Cancer is going to overtake heart disease soon, and that’s only because we’re locked into the somatic mutation theory of cancer. Once you realize the sun is the center of the solar system, you’re going to start to see advances real fast, really effective.
Dr. Mark Hyman: Amazing. But it’s not necessarily just something we have to do alone. I’ve seen data, for example, from Valter Longo who uses calorie restriction diets as an adjunctive therapy for chemo and radiation. It seems ketogenic diets can be used along with chemo and radiation to actually improve their effectiveness. I have a very close friend who had throat cancer, basically, had neck cancer, and was a very poor diagnosis. And he decided to go on a ketogenic diet and get chemo and radiation. Not only did he do great, but there’s been no cancer three years out. He’s also actually had no side effects from the treatment, because of the way that the ketogenic diet protected him against the chemo and radiation side effects.
Dr. Thomas Seyfried: Well, I think that’s an important, because we’re going to go through a hybrid system, because you can’t dramatically change one series of treatments over to another overnight. You’re going to have to gradually go through this kind of a hybrid system where some level of radiation or some level of chemotherapy or even immunotherapies may be enhanced in their action when combined together with metabolic therapy. There’s going to be that hybrid transition. That might be essential, because some of the strategies for the complete resolution of cancer using metabolic approaches alone are not yet completely developed and validated in clinical trials. You will have this interim hybrid approach, like all major technologies that go from one paradigm to another. There’s always this hybrid, transitory hybrid system.
I think we’re going to realize that extremely … And this is what some of our clinics are doing, extremely low doses of chemo managed together with metabolic therapy seem to be far more effective with significantly lower toxicity. Whether that’s radiation or chemo, you can significantly improve the outcome by using much lower doses, and these kinds of things. I think that until we come up with the most elegant and complete way of managing cancer with metabolic therapy alone, I think we’re going to have this hybrid transition period.
Dr. Mark Hyman: What is your conversation with oncologists? You get invited to the oncology meetings to talk to them. What do they say?
Dr. Thomas Seyfried: Well, it’s a variation of things. I think some of them feel threatened sometimes. “What are you going to do? You’re touching my meal ticket here. I do this for a living, and now you’re coming along saying I shouldn’t do what I’m doing.” I think for certain cases like radiation of brain cancer, I think that should be eliminated as soon as possible. I think that’s an outrage. I have published papers clearly showing how the radiation of a patient with glioblastoma elicits the rapid recurrence and death of the patients.
Dr. Mark Hyman: Wow.
Dr. Thomas Seyfried: I provided the metabolic mechanisms by which that is happening, and we show that why the survival of these patients is so poor is because they’re radiating the brain of these patients. Now, that not may be the case for other types of cancers. In those kinds of situations, we may be able to have a more transitional situation. But certainly not for brain cancer. But when you talk to some oncologists, they’re kind of surprised. Most of the oncologists that support our work are those guys that are now retired. It’s kind of like, “Yeah, I knew what I was doing all my life wasn’t the best, and now I realize, but I’m no longer practicing medicine. Now I can pretty much come out and say the things that I would’ve never said if I were practicing.” I see that, and I always have to laugh about that.
Dr. Mark Hyman: Tom, I have a quick question. Being in this field, can you share a few stories before we close of patients who’ve been treated or tried themselves, or what the stories are? I think we’re considering these anecdotes, but anecdotes are really the beginning of hypotheses, and they’re the beginning of actually the scientific research method, which is actually observing what you see and being curious about it, and creating hypothesis. Let’s talk about some of those cases and what you’ve seen.
Dr. Thomas Seyfried: Yeah, the most remarkable one was Pablo Kelly from England, who was written up in all the newspapers over there. He has his own little podcast thing, I think. He came to me in 2014. He heard from Andrew Scarborough, his friend who had a high grade glioma, who took one radiation shot. He said, “I’m out of here. I’m not doing that again.” So Pablo talked to Andrew, Andrew said, “Contact Seyfried.” So he came to me in 2014, Pablo Kelly. He had just been diagnosed with a glioblastoma. And he said to me, “Do you think the metabolic diet therapy would work?” And I said, “Geez, I think it might, but I don’t know. We’ve done it in mice, but we’ve never really done it in a human.”
And he started it and they said, “You’re going to be dead in nine months, Pablo.” His oncologist got really angry. And if you listen to his stories, how they brought him in, they had him, put him … He threw all that stuff off and just went on the metabolic therapy. And his tumor didn’t grow very fast. And finally after no surgery, even had no surgery and nothing, which was really shocking. And then after three years he kept emailing me and he said, “I’m still alive.” In fact, I hadn’t heard from him for two years. He emails me, he said, “Pablo here.” I said, “Pablo, geez, I thought you would’ve been dead. I didn’t know you’d be still alive.”
So then three years after the diagnosis, he did a surgical, and my colleague, some radiologist said, “This is growing, so you probably have to have it debulked.”: So he went in and got debulk surgery for the first time three years after diagnosis. And then we followed him. He has five years of daily, and sometimes more than one day, glucose ketone index. So in the paper that I published, which is in again Frontiers in Nutrition, we put in Pablo’s story. I didn’t write Pablo’s story up until five years after his initial diagnosis. I didn’t want to write something up prematurely and say, “We’re thinking this poor guy dies at little longer than what you’d have expected.” He’s now out almost nine years. He’s still alive.
Dr. Mark Hyman: Wow, nine years.
Dr. Thomas Seyfried: He had a glioblastoma. Yeah, and then we found out that he had IDH1 mutation, which is interesting because it acts like a drug. It’s God’s gift to the GBM patient. It’s a gene that disrupts glycolysis and glutaminolysis. Here’s the crazy thing. There are drug companies out there thinking that that mutation is bad, so they make drugs to target what we consider a therapeutic mutation, and their drugs are killing the cancer patients, some of the patients, faster … It’s nuts. Unless you understand the biology of the disease you’re working with, you really can make real major errors.
But anyway, that story of Pablo, and people can read about him. He’s on British television, he was on newspapers, he has his own podcasts. And then there’s a movie coming out, a documentary that will highlight the stories of all of these kinds of patients that should have been dead that are alive. The documentary is called The Cancer Revolution. It was made by Maggie Jones, another stage four breast cancer person where they metastasized to all her lungs and brain, and she’s still alive, who had done metabolic therapy. Her husband is Brad Jones, a documentary movie guy. And then she says, “Brad, you got to make a movie on this stuff.” So he’s making a documentary, and they’re collecting, as you said, these anecdotes. Well, there’s not a few, there’s now a whole slug of these anecdote guys that are out there.
And the question is, why are we not doing clinical trials to prove that this is a very effective way? And the answer is, we don’t do clinical trials because we don’t have people that are knowledgeable enough to do it, and the hospitals can’t generate revenue doing clinical trials where we’re not using these kinds of drugs. But I think we can work through all of this. I think there will be a way to do this, because you can’t collect so many anecdotal evidences of stage four people that should be dead that are walking on the planet over and over and over again, whether it’s brain cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, all of these different cancers in so-called walking dead people. I mean, they all seem to be getting on with their life. They’re living having a high quality of life. You just can’t suppress this stuff for any longer. I mean, it’s becoming too much. And it’s based on hard science. Once you have the mechanisms and the hard science, we’re going to start seeing it.
And then some people will say, “Well, I can’t believe it until the clinical trial.” They won’t believe it, even with a clinical trial. We’re always going to have the people that’ll never believe this through dogmatic ideology. And how do I know that? Because we did clinical trials on ketogenic diet for epilepsy. And some people said, “We can never use a ketogenic diet for epilepsy until there’s a clinical trial.” So my colleagues did a clinical trial, and they still want to give drugs rather than ketogenic diet. It’s just part of the system. It’s going to happen. I know it’s definitely going to happen. I can’t tell you when, I don’t know. But if we’re still sitting here in 30 years talking about CAR-T immunotherapy and PD-L1, this kind of crazy stuff based on a somatic mutation theory, no, no. Things will definitely change. The field is changing rapidly, ’cause people want to live.
Dr. Mark Hyman: I mean, I think this is one of the most exciting conversations I’ve ever had about cancer. All of us are affected either personally or through family members or friends. It’s really such a widespread condition, and we’re really not winning the war very much. I think we’ve made incremental benefits. Some cancers we definitely have had good cures for, but very far and few between. And I think there is some benefit to CAR-T therapy and PD1, what we call it checkpoint inhibitors. There are improvements in things like cancer vaccines. But I think they’re, again, moving around the edges rather than dealing with the fundamental metabolic issue, which is actually driving most cancers.
Dr. Thomas Seyfried: Yeah. Well, I think though, no question. If I looked at the data for PD-L1 inhibitors and you get about 20% to 30% of people that really do really well. Then you have a majority of people that it doesn’t do anything, and then you have 20% of the people where you get what we call hyper progressive disease, where the therapy kills you faster than the tumor does. That’s called hyper progressive disease. It’s well known in the scientific literature. Okay, so why would anyone want to take a drug that would have a remote possibility of killing you? I mean, this is the truth. This is what happens. Again, people should read the literature about hyper progressive disease. Immunotherapies are based on the somatic mutation theory of cancer. If the theory underlying the treatment is not correct, you’re not going to get the results that you would’ve predicted at the beginning. I have hundreds of people emailing me who tell me how their immunotherapies have not worked, and now they want to do metabolic therapy. I see a lot of those folks.
Dr. Mark Hyman: Basically the message is, start with metabolic therapy. Don’t wait till the last minute and try it after you’ve done everything else, on your last legs. Because metabolic therapy is essentially risk-free. It’s got no side effects, really. Maybe the glutamate inhibitors do, but I think it’s as a whole a very safe, effective, and by the way, almost free therapy, because it’s just what you’re eating.
Dr. Thomas Seyfried: Yeah. Another thing, Mark, listen, it’s very important. If you can pare down the size of that tumor to a few cells that are just hanging on, they become extremely vulnerable to a potential immunotherapy, because there’s where they may all express the same epitope, and therefore the immunotherapy could just blast them out of existence. But you wouldn’t want to do it when you have the whole hodgepodge of cells at the beginning. Bring them down to a small, manageable group of cells by metabolic therapy, and then polish them off with a CAR-T immunotherapy or an immunotherapy. You’re right, everything is bass-ackwards, the way that we’re doing it now. You got to start with metabolic therapy, shrink the tumor down, make yourself healthy, and then come in with some of these more perfected treatments. Makes sense, right?
Dr. Mark Hyman: Yeah, it totally makes sense. Well, thank you so much for your work. It’s really groundbreaking. I imagine one day you’ll be getting the Nobel Prize when people figure this crap out.
Dr. Thomas Seyfried: [inaudible 01:21:20].
Dr. Mark Hyman: And I think you really were out in the wilderness for so long, but now mainstream oncologists and mainstream scientists are now applying this in clinical trials. We’re seeing more data be promising. I think there’s a lot of hope out there, and I think we’re possibly at an inflection point for cancer therapy in the world today. I think it has a lot to do with the kind of thinking that has led your work for so long, and I see we’re really in this kind of very hopeful moment in a very hopeless disease.
Dr. Thomas Seyfried: Yeah, I agree. I agree. Thank you.
Dr. Mark Hyman: Well, thank you so much for being on the podcast. If you, everybody listening, love this podcast, know anybody with cancer, or had cancer yourself, make sure you share it with them. I think this is a very, very important conversation, and is worthy of sharing widely. I think we’d love to hear your comments. Have you used your diet or ketogenic diets or others actually address your cancer? And we’d love to have you subscribe to our podcast whenever you subscribe, and we’ll see you next week on The Doctor’s Pharmacy.
Closing: Hi, everyone. I hope you enjoyed this week’s episode. Just a reminder that this podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you’re looking for help in your journey, seek out a qualified medical practitioner. If you’re looking for a functional medicine practitioner, you can visit ifm.org and search their find a practitioner database. It’s important that you have someone in your corner who’s trained, who’s a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health.