Episode 16: Cancer as a Mitochondrial Metabolic Disease & The Calorie-Restricted Ketogenic Diet with Dr. Thomas Seyfried

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Kara Fitzgerald:
Hi everybody, welcome to New Frontiers in Functional Medicine. I’m Dr. Kara Fitzgerald. Today I have the honor or speaking with Tom Seyfried, who has really done remarkable research looking at cancer, and a wildly alternative approach to addressing it, as we’re going to discuss shortly from the mainstream focus.

Let me just give you some background on Dr. Seyfried. He’s a professor of biology at Boston College. He received his PHD in genetics and biochemistry from the University of Illinois in 1976. He did undergraduate work at the University of New England, where he recently received the Distinguished Alumni Achievement Award. He also holds a master’s degree in genetics from Illinois State University in Normal, Illinois. Dr. Seyfried served with distinction in the United States Army, 1st Cavalry Division during the Vietnam War and received numerous medals and commendations. He was a post-doc fellow at the Department of Neurology at Yale University School of Medicine, and then served on faculty as assistant professor in neurology. Other awards and honors have come from such diverse organizations as the American Oil Chemists Society, National Institutes of Health, The American Society for Neurochemistry, and the Ketogenic Diet special interests group of the American Epilepsy Society.

Dr. Seyfried previously served as chair scientific advisory committee for the National Tay-Sachs and Allied Diseases Association. He presently serves on several editorial boards, including those for nutrition and metabolism, neurochemical research, The Journal of Lipid Research, and the ASN Neuro, where he is senior editor. Dr. Seyfriend has over 170 peer reviewed publications. He’s also author of the seminal book, “Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer”, and that’s published by Wiley Press. You can access his peer reviewed publications on PubMed.

Just a little background in my relationship with Tom, I had the honor of getting to actually shadow you, Tom, I think about two years now. I was up at your lab in Boston College, and you were so generous in allowing me to spend half the day pinging you with questions. You’ve consistently been really generous with our community, the functional medicine community, and, actually, lay people, people suffering with cancer, sharing your knowledge. I’m just thrilled to be with you again today.

Thomas Seyfried:
Thank you, Kara. It’s a pleasure, again, for me to have the opportunity to discuss these issues with you.

Kara Fitzgerald:
Yeah. They’re important and obviously extremely timely. Let’s just jump right in and talk about the origin of cancer. What is it?

Thomas Seyfried:
We’ve done a lot of work on this area, mostly in re-evaluating a lot of the older research on where cancer cells come from. It becomes clear when you piece together all of these various observations from Otto Warburg, Bovary, Ross Kelly and colleagues from the older literature, and a variety of other, newer observations from several various scientists. It becomes clear that the origin of the disease begins with some sort of disruption of oxidative phosphorylation, which takes place primarily in the mitochondria of the cell. This little organelle, that evolved as a symbiotic interaction with another type of cell in this early primitive time on the planet. There has been a symbiotic relationship between the organism that formed the nucleus and the organism that formed the mitochondria.

What happens then is that, during the formation of cancer, this energy forming organelle becomes dysfunctional in many different ways, which then forces the cell to rely on the most primitive, ancient form of energy, which is this glycolytic pathway. What this cell is doing is simply falling back on an ancient pathway for proliferation and survival. During that period of time on the planet, before this symbiotic relationship occurred between these cells, all of the cellular organisms were rapidly proliferating. They would proliferate uncontrollably, unregulated, as long as metabolic fuels were present in the environment. When the fuels ran out, the cell simply died.

The cancer cell is very much similar to this primitive kind of cell. It will grow as fast as it can as long as fuels are available. Targeting the fuels that these cells use to grow seems like a very logical and effective way to shut down the problem.

Kara Fitzgerald:
We’ll circle back to that and talk a little bit more about how you’re doing that targeting. Based on this, would you say cancer is a metabolic disease, or, as is commonly thought, a genetic disease?

Thomas Seyfried:
It’s clear to me, because I am a geneticist and was, I guess you could say, indoctrinated, like almost everyone else in the field, because everyone is told that cancer is a genetic disease. People say that because if you look at the nuclear genome from the genomic studies and the Cancer Genome Atlas, you find every kind of genetic damage in the nucleus of a tumor cell. This is somatic mutations, these are mutations that arise within the nucleus in somatic cells, rather than in germline cells. Yes, when you look at the majority, not ever cancer, but the majority of cancers have all kinds of defects in the nuclear DNA. Then, you combine that with the fact that we know we have some inherited cancers, like those of the Li-Fraumeni Syndrome and those of the BRCA1 and 2 genes that cause breast cancer. They are germline mutations in specific genes. When you look at the rare inherited forms, together with all the genetic damage in the somatic forms, people are led to believe that this is a genetic disease.

When you begin to think more carefully about this, where do these somatic mutations come from? They come from reactive oxygen species, which are mutagenic and carcinogenic. Where do the reactive oxygen species come from? They come from the damage to the respiration. Provocative agents in the environment damage the respiration of the cell, the cell makes mutagenic molecules, these reactive oxygen species, which then cause the somatic mutations seen in the nucleus, which are largely random. There’s no rhyme or reason to the kinds of mutations that you see in the nucleus. This is what one would expect if these are downstream epiphenomena.

When you see all these mutations and you think this is the problem, you focus on that. That, in my mind, is the reason why we’ve made so little progress in managing the disease, because we’re focusing on that part of the problem. Then you think, “What kind of strategies are we using to manage cancer?” It’s basically trying to break and destroy DNA even more to stop the tumor cells from growing. It’s a nuclearcentric attack on the problem. Most of those attacks, radiation, and these toxic chemos, are designed to try to stop DNA replication by interfering with DNA synthesis. This leads to tremendous toxicity and all these issues that you have associated. It’s not really targeting the real problem, which is, how are these cells growing? Where are they getting their energy from? It’s these fermentable fuels. Very few people are focusing on that.

Kara Fitzgerald:
I just want to back up to, you threw out this idea of the provocative agents initiating production of excess reactive oxygen species. In my mind, many different things can be these provocative agents. What comes to your mind?

Thomas Seyfried:
Well, we’ve already defined … This is the oncogenic paradox that was first discussed by Albert Szent-Györgyi, the Nobel laureate who received his awards for Vitamin C. He called it the paradox, and the paradox … Sid Mukherjee in his book, The Emperor of All Maladies, if you look on page 285 and 303, he is struggling in his book with this paradox. The paradox is, how do you get cancer from so many different agents, through a common pathophysiological mechanism? That’s the paradox.

We know, for example, carbon tetrachloride, there’s a number of chemical carcinogens that are in the environment that have been documented as being cancer-causing agents. What these chemical carcinogens do is they go right to the mitochondria and they blow out the energy metabolism, gradually, of that organelle, forcing the cell into a fermentation metabolism and leading to a chronic inflammatory condition, which is an origin of cancer.

We also know many viruses, like Hepatitis, human papilloma virus, HIV viruses, they all are associated with cancer. Now how do you link a carcinogen that causes cancer with a virus that causes cancer? You find out the viruses are all replicating or damaging the energy of the mitochondria. They’re doing the same thing that carcinogens are doing through a different agent, but causing the same problem.

Then you take x-rays. People know x-rays cause cancer, that’s why they avoid x-rays. What x-rays do, they damage respiration. They damage the mitochondria. Then you look at chronic inflammation. We know that if we have chronic inflammatory fossa, in some population of cells in our body, this is a significant risk-factor for the onset of cancer. Inflammation damages respiration, causes the same problem. Now we’re going to BRCA1, and we’re going to Li-Fraumeni. The Li-Fraumeni encodes the P53 gene, the so-called guardian of the genome. This protein is part of the electron transport chain in the mitochondria. That inherited mutation is essentially producing cancer, through the same mechanism that x-rays and all the other things are producing cancer. It’s knocking out the respiration.

Any of these provocative agents … Age, we know that cancer increases with the age of a person. Age just damages respiration. It’s a wear and tear system issue on the body. Things start breaking down. The respiration starts breaking down, and if you combine that with a small amount of hypoxia inflammation, you’re going to increase your risk for cancer. Type II diabetes and obesity creates a systemic inflammatory condition in the body, contributing a risk factor to the development of cancer through damage to the respiration.

Every one of these provocative agents increase the risk for cancer in populations of cells, in individuals that are prone to this, and you get cancer from a variety of different reasons. But, the common pathophysiologic mechanism is damage to the respiration. This is extremely clear. It generates [inaudible 00:12:16]. Then we create all these mutations indirectly, which are random, randomness, which is exactly what you would expect through this pathophysiological mechanism.

The issue here is almost the entire field, the pharmaceutical, the academic industries, and the cancer industries, they’re all focusing on downstream epiphenomena. They’re building therapies for effects, not causes. What do you think the results are going to be? Very poor control of metastatic cancers. We can talk about metastasis. It’s very clear why we’re making very little progress on this disease. It’s very hard to get people to accept what I’m saying, because to accept what I’m saying means you’re going to have to change the strategy by which you address this disease dramatically different from what we’re doing today.

Kara Fitzgerald:
Right. I know we’re diverging. I’ve got so many other basic questions. We’re going to circle back to this, but you’re saying so many really interesting things. What would you say fundamentally is the issue with switching strategy, when what we’re doing is so limited in its efficacy, where we’re putting endless amounts of dollars?

Thomas Seyfried:
The strategy that everyone uses is to kill cancer cells. This is the strategy. You’re trying to develop therapies that are going to stop the proliferation of these cells who have the signature phenotype of dis-regulated cell growth. This is the target. How do you do this? You can use very toxic chemicals, like we’re using today, and radiation. Even the immunotherapies, the checkpoint inhibitors, are still based on the fact that there are mutations in the tumor cells that are blocking the ability of the immune cells to kill them. It’s still based on the gene theory of cancer.

Some of these work well for a few people, but not for most people. They’re horrifically expensive, and they can be associated with unwanted adverse effects. That strategy, the gene theory strategy, is focusing on killing tumor cells based on the understanding that cancer is a genetic disease.

On the other hand, if cancer is a mitochondrial metabolic disease, we know then that these cells are surviving on metabolites that can be fermented, and not respired. Therefore, if we take away the fuels that they use to ferment, which is this primitive pathways, then they should die also, but with far less toxicity. If you know how to transition the body away from fermentable fuels, to say respiratory fuels like ketones. The body can burn ketones, but the tumor cells have great difficulty, because you need respiration to burn ketones. It’s been shown in numerous papers on structural, metabolic, all kinds, that mitochondria in tumor cells are dysfunctional in one way or another.

The strategy of using metabolic therapies is going to be far less toxic and potentially as effective or even more effective than the toxic drug and radiation strategies that we’re using today. It’s just that a lot of people don’t understand it. A lot of people thing it’s a genetic disease. If you think it’s a genetic disease, then you’re not focusing on these other issues, which are the real essence of the problem.

Kara Fitzgerald:
You had mentioned metastasis. In this whole context, how does metastasis relate to the metabolic theory of cancer?

Thomas Seyfried:
This is a very interesting point, because the metastatic cell, the cell that actually spreads through your body and becomes the difficult adversary to control, is derived from the immune cells themselves, macrophages and dendtritic cells, but mostly macrophages.

What is the macrophage? The macrophage is a monocyte, it’s part of the immune system. It’s like neutrophils and these kinds of things. These are the guard dog of our body. If you have a bacterial infection, a wound, or a cut, these macrophages will go in and kill bacteria, they’ll facilitate the reconstruction of the tissue architecture in the process of wound-healing. They patrol through the body. We have different populations of these. We have residents. Every tissue in our body has a resident population of macrophages, because if there’s a local disturbance in the microenvironment, these macrophages will take care of it. Cells die for various reasons, wear and tear. When the cell dies, the macrophage is there to remove the corpse.

Then, you have monocytes patrolling in our bloodstream, so that if we have a cut or an infection, these guys become activated and they’ll hone directly into the wounding area to facilitate the killing of any bacteria, and facilitate wound-healing.

When the energy metabolism of these kinds of cells becomes abnormal, and they begin to ferment … Let me say, these cells can ferment naturally, because they’ve evolved to live in hypoxic environments. If you have a cut and your blood vessels are broken, there’s no oxygen in there. Bacteria thrive in that environment. The macrophages in our body protect their normal respiration and can function in a hypoxic environment to kill the bacteria. When these cells have compromised respiration, they enter into the fermentation process, locked into that process.

These cells are already genetically program to spread and enter into tissues. What the metastatic cell is then, it’s one of our own immune cells that has gone rogue. They proliferate uncontrollably, and they’re already genetically programmed to exit tissues. They don’t respond to anti-angiogenic therapies, these guys live in hypoxic environments. This is why the anti-angiogenic arm of the cancer industry has been such an abysmal failure in trying to target tumors. We’re spending billions of dollars in anti-angiogenic therapies, like Avastin and these things. They’re not going to work, because the very cell that they’re trying to kill lives in hypoxic environments.

When you start to look at cancer as a mitochondrial metabolic disease and you understand the different kinds of cells that we’re dealing with, then most of the stuff that we’re using makes no sense. That’s the reason why we’re having such a big problem. You’ve got to know the adversary. We’ve defined this, we and others, we know what the adversaries are. We know what we have to do to corral these cells and kill them, by taking away the fuel they’re using to ferment.

I think we can do this. I think it’s a very achievable problem. The metastatic cell is one of our own cells. You say, “They inhibit these checkpoint inhibitors, all of our natural killer T cells.” These activated [inaudible 00:19:17] naturally suppress T cell activation. If you suppress them by restricting some calories, they will eat T cells to get energy. We have to know the adversary. We have to know the biology of what we’re dealing with. Unfortunately, the majority of people in the cancer field don’t understand this. This is the reason that explains the lack of major progress. We recognize these things, and this is what we’re going at. We’re going after what we understand.

Kara Fitzgerald:
I want to talk about that. Going after the fuel, just really drilling down to these fundamental lesions here, let’s talk about glucose driving tumor cell growth.

Thomas Seyfried:
We know glucose drives many tumors. There are some tumors that don’t use it, they need glutamine but there are many tumors that are locked into a … We see this by PET scanning. You can see the areas of tumor light up, because the glucose transporters are upregulated. There’s other reasons for this too, but that’s one of the main reasons. They throw out tremendous lactic acid, so we know that. That creates acidification of the microenvironment leading to a wound, like an unhealed wound, which brings in normal macrophages by the way, normal cells of our immune system, that spew out cytokines and growth factors, that are supposed to facilitate fibroblasts to help heal the wound. At the same time, these growth factors are stimulating these neoplastic cells to grow faster.

It’s an escalating situation. The cells are doing what they’re programmed to do, but in the wrong context. This is now fueling greater amounts of glucose. Then what happens is you get into this fermentation profile, which upregulates the pathways for glycolytic fermentation, and you create an environment that’s ideally suited for using glucose and creating an escalating situation for further growth. Another pathway that glucose is used is the pentose phosphate pathway, which produces glutathione through the availability of NADPH.

These tumor cells, even though they make more radicals, have higher degree of oxygen-free radicals because they have damaged respiration. Why don’t they die from producing these Ras? They have such a high anti-oxidant capacity, from both the use of glucose and glutamine, together will protect them from their own Ras, and also fuels their fermentation growth. You have to realize what this cell is doing. Why is it surviving? You throw all these chemicals at it, you say, “Oh, it’s so resistant.” It’s resistant because you’re providing it with all the fuels it needs to survive in a hypoxic environment. This is not a complicated situation.

If you’re looking at gene mutations that are changing and saying, “These mutations are making it resistant,” that’s nonsense. Those gene mutations have very little to do with this. This is a pure metabolic phenomenon, and if people don’t understand that, we’re going to still wallow in this lack of progress.

Kara Fitzgerald:
Right. The gene mutations are definitely secondary. You describe it basically as our immune system perceives this as a wound and gets in to attempt to clean up, and actually, in its effort, becomes part of the problem.

Thomas Seyfried:
Yes. One of the things, where do the metastatic cells come from? This incipient cancers … Some of these metastatic cells can happen very early in the disease, and we don’t even know where they come from. This is called CUP, cancer of unknown primary. CUP cancer will kill anywhere from 5 to 7% of cancer patients. They don’t know where the tumor cells are coming from, they’re metastasizing everywhere. They have a lot of characteristics in common with macrophages.

Under other conditions, where we have protracted, chronic, inflammatory condition, where our macrophages are coming in to heal the wound and the wound is not being healed but is increased. The macrophages are very fusogenic cells. To help wound healing, macrophages naturally fuse with each other. This sometimes is referred to as multi-nucleated giant cells. You see this in a lot of wounded areas, in tissue pathology. If the wound doesn’t heal and you have neoplastic cells, cells that are called tumor cells, they’re disregulated, but they’re not metastatic. They can’t metastasize because they’re not derived from macrophages. They still can form a very aggressive growing tumor, but it’s not metastatic. Those tumors are very easy to cure, because a surgeon can come in and just pluck them right out. There’s a tumor, it’s not metastatic because it hasn’t yet fused. The macs come in and in that environment, can sometimes fuse with these rapidly proliferating stem cells, and acquire the abnormal mitochondria from the proliferating stem cells, which gradually dilute out their mitochondria. These macrophages become neoplastic by acquiring the abnormal mitochondria from the stem cells, and these things go wild.

This is all very clear. It’s clear to me, it’s clear to a number of other people, but it’s not known by the majority of people who work in the cancer field, despite all of the articles that say this.

Kara Fitzgerald:
Let’s start talking about what you’ve been doing with regard to the solution of this aberrant metabolism, in cancer.

Thomas Seyfried:
I outlined how we can explain the majority of observations associated with the origin and progression of the disease. The logical approach would be to transition all of the cells of our body away from, or reduce as much as possible, the availability of fermentable fuels to the tumor cells, which often means that we have to treat the whole body. The whole body is then transitioned away from carbohydrates to ketones.

Ketones are an alternative fuel to glucose. Once we have the body transitioned away from glucose and to Ketones, we now can start to hammer that glycolytic pathway at a much greater intensity. You have to also realize that all the cells in our body use that same ancient pathway in the first part of our energy metabolism. Glucose is metabolized to pyruvate, and then the pyruvate is fully oxidized in the mitochondria to CO2 and water. All of our cells use that first part of the pathway, but most of the cells in our body can shut that pathway down if they burn Ketones, which directly enter the mitochondria and are metabolized for energy.

The first step in cancer management is to transition the body away from glucose to the Ketone. That will put tremendous pressure on the tumor cells, because they use a lot of glucose, and they can’t respire effectively. Already, you’re putting some pressure. Then, there’s other tumor cells, where they use glutamine to a very … Especially the immune cells, macrophages, neutrophils, they are glutamine hogs. When you have burn patients, you supplement the burn patient with massive amounts of glutamine, which is going to assist the energy of our good macrophages to kill bacteria.

The tumor cells are also using this glutamine. Again, you have to be very careful on how you target the glutamine, while at the same time choking off the glucose. This is a strategy that we need to understand. We need to know how we produce this sequential targeting of fermentable fuels without at the same time harming the normal cells of the body. It becomes a fine-tuning, a tweaking of respiratory and fermentable systems, that enhance the health and vitality of normal cells, while putting more and more pressure. We use hyperbaric oxygen as an alternative to radiation, because now we can up the reactive oxygen in the tumor cells to a higher level while reducing them in normal cells, therefore forcing the tumor cells into a apoptotic cell death through reactive oxygen species.

Many of the things that we’re doing are what the traditional standards of care do, but we can do it without toxicity. We can do it while maintaining the high health of the patient and ending up with an end result that we think will be better.

Kara Fitzgerald:
Right. I just want to circle back to the hyperbaric. Obviously we’ll talk about the specifics of the diet, but people are in Ketosis and there’s a limited protein intake. We’re avoiding glutamine. I appreciate that explanation, just based on the fact that I know there’s always much dialogue in my community around using glutamine in cancer patients. You would say that’s directly contraindicated, so thank you for that.

Thomas Seyfried:
Not always. Only for those cancer cells that would use glutamine, which is the majority of metastatic cancers. For those incipient tumors that are primarily dependent on glucose, you might not need to restrict glutamine. Again it depends. Metastatic cancer, in my view, coming from an immune cell that is programmed to use a lot of glutamine, it might not be in the best interest to use glutamine. Maybe low doses, but certainly not high doses. We’re exploring this right now.

Kara Fitzgerald:
Oh, you are, okay.

Thomas Seyfried:
The chapter is not complete.

Kara Fitzgerald:
Good, all right. We’ll definitely stay tuned. You’re increasing reactive oxygen species in the tumor cells through hyperbaric oxygen, and you’re withholding their ability to synthesize glutathione by keeping glutamine down, correct? This is the method.

Thomas Seyfried:
Glutamine and glucose. Glucose, the pentose pathway will provide NADPH, which is a reducing agent for glutathione synthesis. Glutamine will be metabolized to glutamate. Glutamate is a major component of glutathione, and a lot of glutathione is synthesized indirectly from glutamine. You’re reducing the anti-oxidant capacity of the tumor cell, which is already producing more … They’re on the threshold of death anyway, these tumor cells. They’re not tough, they’re not hardy, and they’re not fit. They only appear that way because we create, through the toxic treatments, the most perfect environment that allow these cells to thrive.

It’s just upside down, what we’re doing to try to treat cancer patients. We’re providing the fuels that keep these cells alive. It’s not like the tumor cells are fit. We’re just never targeting what’s keeping them alive. I think that once you understand how these cells are surviving, then it becomes a logical path to remove their fuels and make them vulnerable to reactive oxygen species.

Kara Fitzgerald:
Got it. Now, calorie restriction, is that necessary always for the therapeutic action of the Ketogenic diet?

Thomas Seyfried:
In my view it is. Here’s what calorie restriction does: it lowers blood sugar, that’s guaranteed. It also elevates blood Ketones to a much higher level than an unrestricted Ketogenic diet. If the ketones are an alternative fuel, you want to get as much of this alternative fuel into the normal cells as possible. At the same time, you want to flood the tumor cell with a fuel that it really can’t use well. The best is to get those Ketones as high as you possibly can.

The problem is you’re never going to get into Ketoacidosis, which is a pathological condition. For people who don’t have type 1 diabetes, or even type 2, you’re not going to get into Ketoacidosis. The higher you can get your Ketones … They’ll only get up to 7 or 8 millimoler, which is pretty high in a person, but it’s not in the Ketoacidonic range, which is 15 to 20 millimoler. You’re well below that. You’re still in the normal physiological ranges.

Calorie restriction will allow the Ketones to become elevated. Consequently, the therapeutic benefit of the Ketogenic diet, restricted, will be better than if people eat a lot of fat. As a matter of fact, if you eat too much of this, you can get dyslipidemia, insulin insensitivity, high blood sugar, and actually make the damn tumor cells grow faster. The Ketogenic diet is a medical fuel, a medical therapy that should have the same respect as any chemotherapy would.

You would never treat somebody with cisplatin at a dose that would be lethal to the patient. You want to just respect the Ketogenic diet, just as much as you would respect radiation and any other type of therapy for cancer. Again, there’s a lot of misconception about Ketogenic diets and tumors. It’s not a cure. It’s just one part of the solution to manage the disease, otherwise it’ll backfire on you and make the situation worse.

Kara Fitzgerald:
Duration of the Ketogenic diet, that obviously depends, but any comments there? I think it depends on the patient and their particular tumor.

Thomas Seyfried:
Right now, unfortunately, there are some people out there that have been using it for more than a year, two years and doing well. They’re still alive, this kind of thing. This turns a lot of people off. You say, “Oh my god, for the rest of my life I’ve got to do this diet.” The issue here of course is that our strategy, for managing cancer, will use a cocktail of drugs, procedures, and diets that will all work together synergistically to resolve the disease. When you use the diet together with the hyperbaric oxygen and these various, what we like to term “dirty drugs” … Dirty drugs are great because they can target multiple different pathways simultaneously. We’ll look into some of these kinds of things.

We want this disease to be resolved in the same period of time that the standards of care are being used. We’re not talking about putting people on Ketogenic diets for years. We’re only doing that now because we haven’t put the whole package together yet. Once we get the whole package together, this whole cocktail therapy, we’re going to make cancer manageable the same way they made AIDS manageable. You use a cocktail of different inhibitors of protease inhibitors. You drop the death rate by a massive number.

We’re not saying we’re going to cure the … All we can say is we think we can keep people alive in a healthier state for a far longer period of time. We don’t want people to have to be on Ketogenic diets for the rest of their life. It’s just one part. Nor would we want a person who says, “I’ve taken radiation, and it looks like my tumor is gone.” We don’t want to be radiating these people for the rest of their lives just to make sure that they don’t get this. Everything is how can we accomplish the mission over the shortest period of time and guarantee a longer resolution of the disease, with a higher quality of life? That’s the bottom line. It is definitely achievable.

Kara Fitzgerald:
What are some of the other interventions that you’re thinking about? Is there anything that you can talk about now?

Thomas Seyfried:
Besides the Ketogenic diet, there’s a variety of drugs that will also target the glycolytic pathway. There’s 3-bromopyruvate, the oxyglucoses. You have a lot of different things that by themselves won’t work effectively but for a few people, of course. Then there’s certain glutamine inhibitors and this kind of thing that we’re looking into. You have to be very careful, because glutamine is a very important … Glutaminolysis, the use of glutamine in our body, is involved in so many different pathways like uria cycles and the formation of a lot of amino acids for tissue and protein synthesis. You really have to be careful on how you use this strategy for managing the disease.

That’s part of the excitement in how we’re going to be able to put together the full approach. That’s where the research is. We don’t need anything more. All we have to do is get the right scheduling, the right dosages, and the right timing. This is not … We’re spending billions and billions of dollars on things that won’t work in the long-term. They make people sick, and they cost a fortune. We can manage this disease without costing a fortune and without making people sick. I’m absolutely convinced of this, but very few people are doing this. Everybody thinks this is a genetic disease, infinitely complicated, it’s going to take us years. That’s only because you’re focusing on the wrong thing.

Kara Fitzgerald:
I was talking to Eugene Fine recently, who’s looking at PET scans and so forth and the different tumors and what fuels they’re relying on. He’s commented that he thought some tumors can actually move into relying on Ketones. Is that anything that you’ve seen?

Thomas Seyfried:
We have to look at when we say “relying on Ketones.” Can tumors oxydize Ketones? Yeah, probably. Do they get energy from it? Not likely, because in order to get energy, you have to assume that the mitochondria in that tumor cell has to be normal. No tumor cell has normal mitochondria. I have to admit that the slowest growing tumors, the mitochondrial oxidative capacity, the respiratory capacity, is intact to some degree, in the slowest indolent kinds of tumors that’s the case. You can see in the most aggressive tumors, they don’t even have mitochondria. You can look at EM (electron microscope) examples, and they have very few mitochondria. The ones that are there are all dysmorphic, so you know these guys have to be using a massive amount of fermentable fuels.

It is true that some of the slowest growing tumors do have some level of mitochondrial function, but again, it’s not completely normal. Can they burn? They can probably stumble along a little bit on Ketone, but no aggressive tumor is going to be able to use Ketone, because they don’t have the mitochondria to use it. You look under the electron microscope, and you see that … Look at the EM of mitochondria in aggressive tumors. They have crystalysis, they’re all dysmorphic. You know they can’t use. They’ve got to be fermenting. They can’t be respiring.

There may be some, but they still are going to have to rely more on fermentable fuels than respiratory fuels. Again, how you schedule to eliminate these tumor cells goes through a process. If you can bring these tumor cells down into a single site, an indolent state, they can be excised by a surgeon and the disease can be cured. Again, surgery is also a component for curing cancer. We know that surgeons can cure cancer as long as it hasn’t metastasized. We wanted to bring these more aggressive tumors down into a less aggressive indolent state, where surgery could then have a bigger role. Then, the metastatic cells, we would have to eliminate them through a scheduled targeting of their fermentable fuels. Everything has a plan, it’s just that it hasn’t been fleshed out completely.

Kara Fitzgerald:
Right. I so appreciate you and your team’s work in this area. The mitochondrial enhancement therapy specifically, is that what you’ve been talking about with regard to the schedule and the various interventions?

Thomas Seyfried:
A lot of people are talking about … Mitochondrial enhancement therapy is best for prevention of cancer. If cancer is a mitochondrial metabolic disease, and you keep your mitochondria in the highest level of efficient function, then the risk of getting cancer is going to be massively reduced. Therapeutic fasting, somebody goes on a water-only therapeutic fast for seven days, this is a form of mitochondrial enhancement. Now you’re going to be burning a lot of Ketones.

When the normal mitochondria burn Ketones, they actually reduce the production of reactive oxygen species. Some of the cells that have mitochondria that are not up to full energetic utility, some of these mitochondria will be digested through an autophagy mechanism that’s call the self-digestion. Their products will be recycled and you will reconfigure new, healthy mitochondria in cells where they had wear and tear mitochondria, they’re eliminated. You then repopulate your cell with a healthy mitochondria. This happens under therapeutic fasting. Therapeutic fasting has been known to resolve a number of different kinds of cancers, if you can do it long enough. It’s a very hard thing to do. Most people can’t stop eating or drinking only water for seven to fourteen days. This is not a common practice, but it does work for those who can do it.

Then, there’s another group of people who think maybe not all the mitochondria in a tumor cell are completely dysfunctional, and maybe it’s possible to restore the mitochondria in these early neoplastic cells and return them to a normal state. Then they become growth regulated and join in the society of cells. That’s an interesting concept. I’m not too in favor of trying to reeducate cells. I’m more in favor of eliminating them, so we never have to worry about them again, but that’s certainly a possibility. Of course we know, with mitochondrial transfer therapy, which has been done most in vitro, not in vivo. You can revert completely a tumorigenic phenotype to a normal phenotype if you remove the abnormal mitochondria and put in fresh new mitochondria. Even though the nucleus may persist with all the mutations, the cell is not neoplastic any longer. It’s kind of interesting.

Kara Fitzgerald:
I’m sorry to interrupt you. I just wanted to say to the listeners that I really appreciate your 2015 paper, July, Cancer as a Metabolic Disease in Frontiers in Cell in Developmental Biology, folks. This paper is a free full text. We’ll put a link on the website for you. You can specifically read and look at some of the research around that, returning abnormal nuclei into normal cells and then having the cell be normal, demonstrating that the damaged nuclei have no impact.

Thomas Seyfried:
Other than controlling the development. All those mutations in the nucleus in a cancer cell, people are focusing on that. Then when you put that nucleus into a new cytoplasm, you don’t get the dysregulated cell growth. However, the organism develops with that tumor nucleus only up to a certain developmental stage. Then it aborts, because the mutations in that nucleus, the genes that are mutated are actually required. The products of those genes are required for the continual normal development of the cell.

It’s like anything, all of a sudden a stage 2 is developed, stage 3 is developed, we need the product from that gene. That gene is mutated, therefore we don’t get the product. Therefore, the whole system implodes on itself. The mutations are really controlling the developmental epochs. They’re not causing the dysregulation of the growth. The dysregulation of the growth is coming from the fact that the mitochondria, which actually control the growth of the cell, that organelle is dysfunctional, so these cells are fermenting and growing out of control. It’s not related to the mutations of the nucleus. It’s very interesting.

Kara Fitzgerald:
It’s really interesting.

Thomas Seyfried:
When you get into putting all this stuff together and understanding how all the parts of the puzzle fit, you have to scratch your head and say, “What the hell have we been doing for all these 50 years?” It’s insane, what we’ve been doing in this cancer field. This is a manageable disease. We can live with it. We can manage it. I think we can even resolve it for the majority of people. We’re just doing everything upside down and in the wrong way. I don’t know how long it’s going to take for people to come to know this. Once they do, we’re going to have progress.

Kara Fitzgerald:
It does seem like there are more people looking along these lines, more scientists researching along these lines. Would you say that that’s true? Have you noticed some movement towards answering these questions with you?

Thomas Seyfried:
Oh yeah. There’s no question about it, but you often see of those guys who are locked into the gene theory, their argument is that the abnormal gene mutations are controlling the dysregulated metabolism. Again, the gene theory is dominant because the abnormal metabolism is the result of the gene mutations, not the reverse. This preserves the dogma and keeps everybody focusing on the gene mutations. You have to say these oncogenes, they’re just upregulation of cells that drive fermentation pathways. When you put new mitochondria there, the oncogenes turn off.

The whole argument is that this is a type of mitochondrial metabolic disease, and if you want to resolve the disease, you best understand that. Don’t beat around the bush wasting millions of dollars studying signaling pathways and trying to figure out all this kind of stuff, when all you need to do is take away the fermentable fuels. That is a much more achievable mission than trying to understand how gene mutations are controlling a thousand different signaling pathways. You see what I’m saying? Do you want to study and putz around with the disease for the next hundred years, or do you want to resolve the disease? It’s a very simple question.

People will publish all these papers in Science and Nature, “Look at this pathway, look at that pathway. Watch the way this mutation controls that.” This is academically exciting and very interesting, but it’s not going to help the guy dying in the clinic. You want something that’s going to help that person who is suffering from the disease now, not a hundred years from now. We can do that if you focus on the mission, to manage and get rid of these tumor cells while not harming the rest of the body. We can do that.

Kara Fitzgerald:
You were working with exogenous ketones. Are you still doing that? Are you guys still working with that therapy?

Thomas Seyfried:
Yeah. Exogenous ketones could be part of the cocktail that will eventually be used for the resolution of the disease. The problem is, of course, that getting these ketones in sufficient quantities to have a therapeutic benefit. The ketone that needs to be used is D-beta-hydroxybutyric acid, not the racemic DL mixture, but the D form. The D form is very difficult to synthesize. Richard Veech at the NIH has a patent for synthesis, but it’s very hard. It requires a lot of work to actually make D beta-hydroxybutyric acid. It’s a sophisticated biochemical reaction.

When people use ketogenic diets and do therapeutic fasting, our liver predominantly makes the D beta-hydroxybutyrate. We make that drug naturally through our own biochemistry. We make that metabolite naturally, as a breakdown product of fat. Our liver can do this. To synthesize it as a chemical in the lab to make a drug from D beta, it’s not that easy. That’s the kind of ketone supplementation you would need to prevent the tumor cells from using it effectively and also to raise levels high enough to keep our normal cells healthy. Yes, but it’s part of the strategy. We plan to use that, we plan to build cocktails with that to determine how effective that is when we add it to the cocktail mixture.

Kara Fitzgerald:
Good. All right, we’ll stay tuned. Cancer is preventable, would you say?

Thomas Seyfried:
Absolutely. Cancer is probably one of the most preventable diseases. In theory, it’s very preventable, but in practice it’s extremely difficult to prevent. The environment that we live in, a technological Western society, produces an environment that contributes to the disease. A lot of that has to do with diet and nutrition. We eat huge amounts of nutritionally deplete foods that are very high in carbohydrates, that create systemic inflammation in our bodies and harm the respiratory systems of our cells. We are exposed to chemicals, foods, a whole variety of different things that damage our respiration and put us at risk for cancer.

How many people are going to do therapeutic fasting and then when they eat, they eat only the purest of organic foods? Carbohydrates are fine. Carbohydrates don’t cause cancer. Many people say sugar causes cancer. No, sugar doesn’t cause cancer. Sugar will lead to an inflammatory condition, and the inflammatory condition can put you at risk for cancer by leading to dyslipidemia, type 2 diabetes, and a variety of the other things. If you have cancer, the sugar will certainly facilitate its growth, but sugar is not considered a carcinogen. The idea of complex carbohydrates that are broken down slowly, these non-glycemic carbohydrates, these are fine.

People can transition. A lot of people are doing this. They’re going to these organic farms, they’re getting all this organic meat. Meat doesn’t cause cancer, but it can certainly provoke it if it’s all full of chemicals and hormones, this kind of thing. Genetically modified foods can put you at risk for increasing damage to the respiration. We’re in an environment that creates a situation that puts ourselves at risk for cancer. If you want to prevent cancer, you’d have to replace a lot of the things that we would normally find ourselves eating with other things. Then, your risk for cancer would go way down.

All you have to do is look at the animals in their natural state, for example, the wolf. The wolf eats meat. It’s a meat-eater predominantly. In the wild wolves don’t get cancer. Cancer is extremely rare. The dog was bred from the wolf. The dog is full of cancer. Cancer in dogs is very high. What are they eating? They’re eating Purina dog chow, full of carbohydrates, unnatural things that these dogs are eating. A lot of these chows have all kinds of grains in them. Dog did not evolve to eat grain. When was the last time you saw a wolf going through a corn field gnawing on a corn on the cob? You don’t see this.

We feed dogs this kind of stuff. Then they’re all full of cancer and we’re wondering why. Then, we’re treating them with the same toxic chemicals we treat humans. Dogs get sick, costs them a fortune. We’re seeing that when we put dogs on natural organic foods and calorie restricted ketogenic diets, these tumors disappear. We don’t even need drugs most of the time. Clearly, this is a very preventable disease. It’s just the environment that we put ourselves in creates this incredible risk for cancer.

Kara Fitzgerald:
Yeah, absolutely. Based on what you’re doing, we’re actually seeing some nice reverses. In my practice, I’m prescribing the calorie restricted ketogenic diet for cancer patients and for some other inflammatory conditions. I know that, Tom, I really took this on and evolved. I have a good nutrition team now, and they’ve become versed in doing that. People find me over at your site. I know that many patients reach out to you. There’s also a lot of clinicians interested in really understanding this and getting training around how to implement it. Where are you referring patients these days? For the clinician who wants to move into using these therapies, the diet, maybe hyperbaric oxygen, what are you advising?

Thomas Seyfried:
This is a difficult situation, because there are nutritionists like yourself, a lot of MDs, naturopathic physicians, who practices seem to be more in line with these kinds of approaches. They seem to be far more open to this. There’s a lot of MDs that are, too. There’s a lot more people that are becoming aware of this.

One of the things that physicians now need to know … I think NDs have always been into a lot of blood work. They like to look at a lot of blood, sometimes more than the guys down at the major hospitals look at blood work. You know what I’m saying? We’re seeing certain things now, we’re beginning to see elevation in vitamin D using restricted Ketogenic diets. As I said, the glucose Ketone index calculator that we published in Nutrition and Metabolism, the physicians need to use more information from a patient’s blood work to keep them on track for the kinds of therapies that we think will be effective.

You want to keep triglyceride levels low, you want your HDL and LDL to be at approximately the same ratio, which is really good if your HDL and LDL ratio are about the same, and you want the blood work to look pristine, that you would consider, “Wow, this is the blood work that I see for a really healthy person.” Then you use the biomarkers of ketone blood glucose monitoring with the blood work monitoring, and then using that information, at least we’re keeping the patients recognizably healthy. While we begin to treat them, we’re going to use drugs, hyperbaric oxygen, and various approaches that will maintain a healthy blood work and keep a high state of health in the patients themselves.

We don’t want people’s hair to fall out. This is absurd. Anytime you see a cancer patient who has lost hair, that person has been mistreated. The person treating that patient has no clue as what they’re doing. Hair for a patient should not fall out. That’s a clear sign that somebody doesn’t know what they’re doing when they’re treating this person. You need to have matched these blood works, because then you can see, when we add on the cocktail drugs and therapies, hyperbaric oxygen, can be very healthy when the patient is in a state of therapeutic ketosis, but can be very dangerous if that patient isn’t. There are hyperbaric oxygen centers that are now being set up where patients are put into therapeutic ketosis and then placed into the hyperbaric chambers. Then, together with certain drugs that work against glycolysis and glutaminolysis, this package could be extremely therapeutic, without harming the patient and causing the maximum destruction of the tumor cells while enhancing the health and vitality.

MDs need to know the strategy. I have to be honest with you, we’re still working this out. Funds for this kind of research are so limited. It’s very hard to get money to do this kind of research, because it’s not considered by the academic industry, to be sexy stuff. This is not sexy science. This is practical science, science that’s actually going to work and have a direct effect. It doesn’t talk about some esoteric signaling cascade. The NIH seems to get really excited about these esoteric signaling cascades. Getting funds to put these cocktails together and then establishing a pre-clinical system … What we do is we vet everything at a pre-clinical model system, making sure that the cancers are resolved without harming the mouse, and then that can be immediately translated to the physicians, who apply that same strategy to their patients.

Again, each patient is going to differ a little bit. He may respond better to one combination of the cocktail, where another patient may respond better to the different combination. It’s a learning process on the part of all of us — the basic scientists, as well as the physicians, and as well as the patients. It’s a team effort that will be used together to strategize the management of cancer. Once we have a better understanding, we’ll be able to streamline all this to make it much more efficient for each person.

We’re not there yet. This is just the cutting edge. We are at the beginning of a new phase of how we’re going to deal with this disease. First of all, it requires an understanding. Second of all, how do we put it into practice? That’s where we are right now. You guys are the ones putting it into practice.

Kara Fitzgerald:
Yeah. There are many of us really looking at it, prescribing it, and paying attention to outcome. It’s been mixed. Some people are able to jump in, follow it, and get into pretty aggressive ketosis numbers quickly and see their index at an appropriate level. Other patients really struggle. It really has a lot to do …

Thomas Seyfried:
The other thing, Kara, I want to mention, is stress management. I can’t tell you how important it is for stress management. Many cancer patients have anxiety. The anxiety leads to elevated glucose, and what happens is this is counter-productive to managing cancer. Stress management becomes part of the solution to this problem. You’ve got to have these patients in as low stress as possible. That’s when the metabolic therapies will work best. Massage therapy is very important, I think, and it makes hyperbaric oxygen with therapeutic ketosis altogether working better.

We haven’t even begun to … When you guys begin to treat your patients, you have to use the correct drugs, not toxic drugs. You need to use drugs that are going to work together synergistically with the metabolic therapy. Avoiding toxicity is a key component of effective disease management. So many of these toxic chemicals, these platinum drugs and these other toxic things, toxic radiation, is not part of the solution. Despite what people think, it’s not going to be the part of … On the other hand, there will be patients who simply cannot take charge of their own destiny. They don’t want to be involved in any part of this. Therefore, the current toxic standards of care will always be needed for that population of patients who do not choose to take part in their own health management. We’re always going to need toxic drugs and radiation to take care of that population of patients.

Kara Fitzgerald:
There are plenty of patients who come to me who want me to co-manage them. They are on the toxic protocols, and we’re still doing our best.

Thomas Seyfried:
That’s another thing. We don’t know because a lot of these toxic chemicals also dovetail in with the steroids, this kind of thing, to give them an appetite. Why are they losing their appetite? All these kind of things are counterproductive to the management of cancer, without toxicity. They think, “I’m going to use a Ketogenic diet, together with some toxic drug.” It might be okay. I’m not going to say it’s not. I just think why don’t we marry the Ketogenic diet with the kind of drug that’s not going to be toxic? Then they say, “Where’s the clinical trials on this?” Who’s going to support the clinical trials if you’re not interested in that strategy in the first place?

It’s going to be a steep learning curve here for this. It’ll happen. It’s going to happen, because we can’t continue to do what we’re doing. It doesn’t work. I also want to acknowledge the Travis Christofferson’s Foundation, the single cause, single cure foundation, which is one of the few private foundations that are actually interested in funding and supporting metabolic therapy for cancer. They’re not interested in these toxic drugs, immunotherapies, and this kind of stuff. They’re interested in how can you manage cancer, just like I’m saying, non-toxically, using a cocktail of drugs and procedures that all work synergistically together to manage the disease without harming the patient.

I think this is the strategy. People should be excited about this, to know that we actually can do this. The problem is that most of the funding and most of the discussion is in a totally different sphere. I think people have to come to know this. I think patients, you’re right, more and more people hear about metabolic therapy, they come to their physicians and say, “I’d like you to tell me about metabolic therapy.” They don’t know, because don’t forget, the patient is the ultimate consumer. They are the ultimate consumer of the therapies that will be delivered. They have to have some knowledge-base, and they’ll begin to hear about it through the success of some people who are doing these things.

Kara Fitzgerald:
It’s getting out. It’s definitely traveling. Folks, I will have the website URL for Single Causes, Single Cure, as well as Dr.Seyfried’s contact information, his e-mail address, with this podcast. I feel like this is just a beginning of a very long conversation. We’re already over an hour, and there’s so much more to be talked about, Tom. Thank you for joining me today. I know our paths will continue to cross, and when we’re ready for the next level of discussion or new stuff to report, I’d love to have you on the podcast again so we can keep clinicians in the loop, those out there who are interested. Thank you. Thank you for your work.

Thomas Seyfried:
Thank you very much. It was nice talking to you again, Kara, and I’ll sign off now.

Kara Fitzgerald:
Okay.

Thomas Seyfried:
Bye.

Kara Fitzgerald:
Take care, bye bye.

Thomas Seyfried:
Bye.

Thomas N. Seyfried is Professor of Biology at Boston College, and received his Ph.D. in Genetics and Biochemistry from the University of Illinois, Urbana, in 1976. He did his undergraduate work at the University of New England where he recently received the distinguished Alumni Achievement Award. He also holds a Master’s degree in Genetics from Illinois State University, Normal, IL. Thomas Seyfried served with distinction in the United States Army’s First Cavalry Division during the Vietnam War, and received numerous medals and commendations. He was a Postdoctoral Fellow in the Department of Neurology at the Yale University School of Medicine, and then served on the faculty as an Assistant Professor in Neurology. Other awards and honors have come from such diverse organizations as the American Oil Chemists Society, the National Institutes of Health, The American Society for Neurochemistry, and the Ketogenic Diet Special Interest Group of the American Epilepsy Society. Dr. Seyfried previously served as Chair, Scientific Advisory Committee for the National Tay-Sachs and Allied Diseases Association and presently serves on several editorial boards, including those for Nutrition & Metabolism, Neurochemical Research, the Journal of Lipid Research, and ASN Neuro, where is a Senior Editor. Dr. Seyfried has over 170 peer-reviewed publications and is author of the book, Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Wiley Press). His full list of peer-reviewed publications can be found on PubMed.