Ketogenic Diet – The Background Behind It

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Press-Pulse:

A non-toxic therapeutic

Strategy for the metabolic

Resolution of cancer 

Thomas Seyfried.

 

Where are we and where are we going with this disease?  Well, here is data from the American Cancer Society.

The Percentage increase in cancer death, is greater than the increase for new cases!

Year New Cases Deaths / Year Deaths / Day
2013 1,660,290 580,530 1,590
2014 1,658,370 585,720 1,605
2015 1,658,370 589,430 1,615
2016 1,685,210 595,690 1,632
2017 1,688,780 600,920 1,646
% increase 1.7% 3.4% 3.4%

As you can see the rate of increases in deaths is twice that of new cases, and we can talk about all kinds of things, but until we actually reduce these numbers, we have a lot of work to do.

The question, of course, is why do these numbers continue to increase?  The more money we spend on cancer, the more cancer we get. This is an abomination.  You mean, to tell me, after all these years, we have not been able to reduce the death rates?  We’ve heard from some of the others, that it’s going to go out of control here in several years.

So, what’s responsible? This failure.  This abysmal failure in our ability to manage this disease? A lot of it has to do with how we view the origin of the disease, because it is my opinion, that if we understand the origin of the disease, we will be able to manage the disease more effectively.

We have two conflicting views, on what cancer actually is. Is cancer a nuclear genetic disease, according to the somatic mutation theory?  Which is the dogma that drives the majority of the research in the cancer field, or is it a mitochondrial metabolic disease. Because as you can see, we have a Mitochondrion, and we have a Nucleus and both of these organelles in the disease are abnormal.

Now what I did, was I collected, over a decades worth of research, various observations from the literature that was asking specific questions about how a cancer nucleus might direct development, and I put together these papers, these observations.  I suggest, if you are interested, you should read this paper very carefully, it is one of the most recognised and viewed papers in this journal. It was striking to find that there was massive evidence to indicate that cancer is not a genetic disease.  This is the figure that we generated to summarise the dozens of reports that were never put together except this one time.

When you put them all together for the first time, you are able to see the relationships. So, in this slide, we know, normal cells beget normal cells.  Tumour cells beget tumour cells.  So, we know that there are many mutations in the nucleus of the tumour cells, and we know that the mitochondria are defective in tumour cells.  In structure, number and function. 

But what is responsible for driving the of the neoplastic phenotype?  Is it the mutations in the nucleus or is it defects in the mitochondria?  The experiments show,  that when you move the cancer nucleus into a new cytoplasm that has normal mitochondria, you get normal cells, normal development, sometimes you can clone a whole mouse or a frog from the nucleus of the tumour cells that contains, the “so called” driver mutations that are supposed to drive the disease, but it doesn’t. 

On the other hand, if you take the normal nucleus and put it into a neoplastic cytoplasm you end up with dead cells, or tumour cells.

This data, from these experiments, are the strongest evidence available anywhere to say that cancer is not a nuclear genetic disease.

So, with that knowledge, how do we now view the nature of cancer?  If we are going to correct this disease, we need to understand the origin of the disease.

 

What we have here, now if you focus on the left, the mitochondria, and we have this oncogenic paradox which has plagued the field for decades, which was first pointed out by Albert Szent-Gyorgyi.  How is it possible that all these provocative agents from the micro environment or from inherited genes could possibly cause cancer through a common pathophysiological mechanism. The answer is, these different agents, carcinogens, radiation rare inherited mutations, viruses.  They all damage the respiration of the cell, producing reactive oxygen species which are mutagenic and carcinogenic.

So the mutations that we see in the nucleus, are downstream, epiphenomena, of the damage to the respiration.  The respiratory capacity of the cell now suffers.  The cell says, “I’m suffocating” which then sends signals to the nucleus, upregulating oncogenes which are transcription factors for substrate level phosphorylation which is a fermentation metabolism.

So what happens then, is that the green line goes down, which is oxphos, the breathing of the cancer cell. The red line which is substrate level phosphorylation which occurs in glycolysis in the cytoplasm and in the mitochondria through amino acid fermentation.  This is driven by oncogenes which are bringing in the fuels to drive the fermentation.

So, then we can put together all of the major factors and findings in the disease in light of a mitochondrial metabolic disease.  So you have the Warburg effect and mitochondrial fermentation and the Warburg is as Otto Warburg Said “Is an effect” of damage to the respiration in one way or another.

Then what happens, the first three, Hanahan and Weinberg hallmarks, the cell enters the default state.  The default state is the state that the cell is in when it is no longer under active control.  This is the state that cells were in before oxygen came on the planet.  All the cells were fermenting.  They fermented as long as fuels were available in the micro environment.  Then they would die when there were no more fermentable fuels.

These cells are falling back and these hallmarks are simply the expression of what these cells were doing before oxygen came on the planet.  Now, they throw out metabolites into the micro environment and that leads to angiogenesis.  So, angiogenesis is simply a response to the inflamed wound in the micro environment.

What controls the cell death?  Apoptosis, the mitochondria is the kill switch for the cell.  So if the kill switch doesn’t work, the cells evade apoptosis then the key thing here is metastasis.  How do we get metastasis?  Where are these metastatic cancer cells coming from?

 

What we now know, is that Cancers will start in epithelial cells, and they begin to express this fermentation behaviour and you see this population of blue cells and they start to ferment.  This solicits a response from the immune system to say we have an unhealed wound.  The immune systems come in, the macrophages, to try to heal the wound. They throw out growth factors and cytokines to try and heal the wound but they make the situation “even worse”.  In the wrong context then further, to try and heal the wound, the macrophages are very fusogenic.

To facilitate wound healing, they fuse.  So the very cells that are trying to put out the fire, are actually becoming part of the fire.  Their cytoplasms are being deluded with abnormal mitochondria from the stem cells. Which the stem cells cannot metastasize because they are not genetically programmed to do that.

So, what we end up with, are these hybrid macrophages (fused hybrids) which are now genetically programmed.  The macrophage is genetically programmed to enter and exit the circulation.  Survive immune attack.  It is one of the most powerful cells in our bodies.

What we have now is rogue macrophages.  These guys live in hypoxic environments, so anti angiogenic therapy is not going to work to kill those kinds of cells.  The other thing is, they love glutamine.  OK, so they are part of our immune system, they are glutamine hogs.  They can survive immune attack.  They can do all kinds of things.  So, we are dealing with one of the tuffest cells.  And this is the origin of metastasis.

I will now illustrate some of these things with Glioblastoma.

 

As we know, this is a terrible disease, poor prognosis, no effective therapies.  Composed of multiple cell types, that’s why we call it multi forming.  Different cell types, different kinds of stem cells neoplastic mesenchymal microglia.  It is highly invasive, according to “Secondary Structures of Scherer” and it doesn’t happen often, but when GBM cells get out of the brain they are highly metastatic.

 

Here is an example of Glioblastoma.  You can see the compression of the ventricles.  This is the gross picture, these cells have already migrated through the brain.  They go around the blood vessels, you can see the tumour cells around.  They use the blood cells as kind of a railway track system throughout the brain.  It’s very hard to control this kind of a tumour and most patients die from intracranial pressure.

 

One of the things we know not only in GBM but in most cancer cells, regardless of what tissue they come from, the mitochondria are abnormal.

This is GBM Mitochondria with the christane missing.  The stripes that you see, that contains the proteins and the lipids of the electronic transport chain.  So, if the very structure is missing, there is no way that this organelle is going to produce energy through oxidative phosphorylation, and consequently it’s going to have to ferment, in order for the cell to survive.

What you have then, is you have a powerful fermentation in the matrix of the mitochondria and you have a powerful fermentation in the cytoplasm and that is what is driving the beast.  The beast is being driven by fermentation.

We know of no tumour cell that has been found, those stripes also contain cardiolipin a p-lipid in the electron transport chain.  No tumour has yet been found, (published anywhere in the literature) showing that they have normal content, or composition of  cardiolipin, therefore, they are going to have to ferment.

So, what are they fermenting?  They are fermenting glucose, and they are fermenting glutamine.

 

Glucose on the top, glucose comes in through the transporters, that are upregulating cancer cells, they generate energy through the Embden-Meyerhoff pathway they throw out lactic acid, they also generate antioxidants, they are precursors for DNA Rna synthesis.

Glutamine comes in on the other side, Glutamine, the M. I. Nitrogen is used for nucleotide synthesis. The glutamate can be dumped out and also used it comes into the mitochondria and generates energy through the DCA substrate phosphorylation in the T.C.A. Cycle.

So, these two fuels are the drivers of the beast.  If you don’t control these fuels…. “and” they also prevent, and cause, resistance to chemo and radiation, because the fermentation pathways are so powerful it protects these cells from that.

So, in order to control cancer you’re going to have to remove the fuels of fermentation, which are basically glucose and glutamine. How do you do that?

Well, let me tell you what we are doing, before I tell you how you should do it.  Let me tell you what we are actually doing.

This is a standard of care, what we have here is a cartoon showing what we generally do now for treating Glioblastoma in the clinic.  We Immediately surgically resect. Creating a nice wound, a wound now, that’s going to give the inflammatory cells an opportunity to grow.  And then we irradiate, and we break apart the glucose glutamine cycle.

This is very important to understand.

So, we’re going to free up the very powerful fuel that is going to drive the beast, and then when this kind of treatment starts to cause the brain to swell we give them Dexamethasone, and we have heard how not good that is.  So, we give Dexamethasone which elevates blood sugar.

What we have done, essentially is created a system, where we have provided, the very fuels that are driving the beast.  By the very standards of what we are doing.

Many of these tumours are infected with human Cytomegalovirus which is a supercharger for using glucose and glutamine we create the perfect storm of adverse effects in the brain of the patient being treated for Glioblastoma.  What do you think this kind of treatment is going to do for the outcome of these patients?  There’s the results.

Radiation alone, zero survivors, with Telazolamide a toxic alkalizing agent we have a little bit better progression free survival, but overall, this is abysmal.

This is what I would expect, if what we were doing to these patients is based on the mitochondrial metabolic theory.

OK.  So, let’s change the system.  If we know, that this disease is a mitochondrial metabolic disease, how can we best eliminate and treat the disease?

We have come up with this idea of Press-Pulse, it’s taken from the field of Paleobiology and was considered the mechanism responsible for the mass extinction of organisms on this planet.

These mass extinctions have occurred, only, when two unlikely events occurred simultaneously.  We have a press that puts a lot of pressure on the population, and then we have an acute pulse, and together, the press and the pulse causes an extermination of populations.

We adapted this concept, to manage cancer, and here’s our paper that just came out recently.

So we have this vitruvian  man, on the  left he’s full of cancer, in the middle he’s becoming managed, and on the right he’s resolved.  So, how are we going to do this using the concept of press pulse from the field of Paleobiology, we use ketogenic diet, restricted.  Ketone supplementation.  Ketogenic diets will lower blood glucose, one of the drivers of the beast, and ketones are up-regulated which are a none fermentable fuel. So the ketones are really there to help the normal cells stay alive and function pushing those blood sugars to their lowest possible levels.

You don’t have to worry about hypoglycemia if you are in therapeutic ketosis.  At the same time we use stress management.  Many of these cancer patients are freaked out. They are all emotionally upset, we use exercise, we use yoga, we use music therapy, and all kinds of things.

You’ve got to keep that patient in a very calm set of emotions and then, we pulse with glucose inhibitors, glutamine inhibitors, and hyperbaric oxygen.   We think hyperbaric oxygen can replace radiation.  Why are you going to irradiate somebody when you can use hyperbaric oxygen, when it does the same thing?  So, basically, we’re going to press, and pulse, scheduling timing and dosages and the patients will have these tumours degraded logically and none toxically so that they will emerge from the therapy healthier than when they went in.

We can achieve management without toxicity, and that’s the key.  That’s the key you have to recognise.

So, we started to test these hypotheses and here is our attempt to manage this.

In the standard, high carbohydrate diet, these cells can’t grow any faster.  On the high carbohydrate diet, they move from one side of the brain to the other side of the brain as fast as possible, with the invasive property.  We hit them with everything, we hit them with ketogenic diets, we hit them with calorie restriction, fasting, all this kind of stuff.  We were able to significantly reduce the invasive property of the tumour but we weren’t able to kill it.  What’s going on here?  We took all the glucose, as much glucose as we got out. We have anti-angiogenic therapy, there’s no more powerful angiogenic therapy than calorie restriction, and we wrote a papers on that, we have data to prove that.  It was anti-inflammatory, we hit them with everything and the tumour is still there.  So, we said, what the hell is going on here? We’re doing everything and we said, what about glutamine?  Does the ketogenic diet or the calories target glutamine?  The answer is no.  OK, what happens when you target glutamine?

So, we tested this hypothesis using a glutamine inhibitor called DON.  It has been used in the past, sporadically for people with cancer.  Children with leukemia did very well on it.  Other people didn’t because they didn’t target the glucose, and I will show you the evidence for this.  So, what this drug does, it stops TCA cycle Sub Level Phosphorylation and halts DNA and RNA synthesis.  So this is a very nice kind of drug that’s going to shut down the back door.   Because, we shut down the front door, and these cells are still alive, because we didn’t do anything to the glutamine.  So what happens when we hit the glutamine?

Here is our experimental design.  We put the tumour cells into the mouse’s brain and we let the tumour wait three days, because now it’s going to be a raging GBM and then we put them on a therapeutic fast for 18 hours.  Then we re-feed them, either the high carb diet, or the ketogenic diet restricted and we pulse with DON.  Boom, Boom, Boom, every other, couple of days, and of course the guys eating the high carbohydrate diet are dying at fifteen days.  So this is a nice experiment, you can get the whole GBM study done in fifteen days.  The guys on the standard diet are dropping dead or they are getting really morbid.  Then we examine the mice.

These cells are also labelled with luciferase so we can see them under the bio luminescence, and you can see standard diet, you have to have to put sunglasses on there’s so much light.  The ketogenic diet, just a little bit. But you put the diet with the DON and you get no light.  Alright, we blasted these things out.  They don’t have any light in the brain.  The mice are really healthy.  They’re really looking great.

Here is the diet, versus the diet with DON, and the low little bars there are background.  So they’re not really any living cells.  There was one guy that we took him off the drug for a couple of days, and you can see that he was the only guy that had a little bit of light.  Mouse number six there.

The other thing that we found, that is really remarkable is that, when you give the drug, in the presence of the diet, you get three times more drug into the tumour, than if you give the drug in the high carbohydrate diet.  So, the ketogenic diet is essentially facilitating the deliver of the drug to the tumour, so you don’t have to use as high a concentration and can keep the toxicity down.  This drug doesn’t have much toxicity when used at the concentrations that we do.

Now what’s going on inside the brain of this mouse that’s being treated?  So, here you have on the left, the high carb diet, and in the middle you have the diet with the DON.  The tumour cells could not be any more invasive or healthy in the high carbohydrate diet.  You want your tumour to grow fast?  Get that blood sugar up. Get that blood sugar up as high as you can and those tumour cells will grow super fast.  You take the sugar away, and you stop the invasion.  You see that white part of the brain? That’s the clean brain. And the tumour cells are not as invasive, and they also have more spaces in between them.  So it’s very interesting, the diet is in fact having some impact on the way these tumour cells are growing in the brain.  But on the right side you get a massive Mitotic Catastrophe!  We slaughtered those tumour cells by taking away their glucose and taking away their glutamine, slaughtered them!  And that accounts for why we have no light, in the brain.

Then of course I told you, these cells are highly metastatic outside the brain.  Just like a human GBM.  It doesn’t happen often, but if GBM cells get outside, they metastasize throughout the system.

Our work with Angela Poff and Don D’Agostino we were able to show that when we put the cells into the flank, they spread throughout the whole mouse.  We used hyperbaric oxygen in this case, and hyperbaric oxygen by itself, it didn’t do too much, it was a little bit effective, and the diet by itself was a little bit effective, but you put the two together and hyperbaric oxygen, because now we’re taking away the shield against antioxidant defence only after you remove some of the protective glucose from the diet.

Now we heard earlier today, we like to see the face of people who have experienced some of these treatments.

This is Pablo Kelly, who contacted me back in August 2014 when he was diagnosed with a Glioblastoma, so Pablo, a young man, twenty eight years old rejects standard of care.  He said, I don’t want any radiation, I don’t want any chemo, I don’t want anything.  Except metabolic therapy.  So, I said, OK, do this, do that, he apparently did it and what happened was, he had an inoperable GBM and then after two and a half years, which was just this last winter.  Pablo’s tumour now becomes resectable.  So, he goes in, and has his tumour resected and the last I heard from him was in June 2018, he has no evidence of cancer in his brain.

Now he’s out four years,  and he’s doing fine.  His quality of life is super high, he’s now married with young child.  So, what’s going on here? A three year guy for GBM is what we call a long term survivor.  Now the question is, is Pablo Kelly the exception or is Pablo Kelly the “Rule”?  It’s my personal opinion, that Pablo is alive, because he avoided those therapies that are going to increase glucose, and glutamine in his brain.  That’s my personal view, and I think Pablo is just a pioneer in this field.  We are going to get many more, and we are getting them like that.

Now here’s our most recent paper that we just published in Cureus with our colleagues from Turkey and they’re using a press pulse strategy based on our concepts.

This is for triple negative breast cancer, and this woman came in.  She was in her thirties and you can see on her left breast she has a large tumour.  This is triple negative breast cancer, that had spread to her liver, and her abdomen and we put her on a combined ketogenic diet with some very low dose chemo.  Ketogenic Diet, Hyperthermia, Hyperbaric Oxygen and insulin potentiation therapy.  What we do is pounding down her blood sugar levels.  She has a high quality of life, no toxicity and you can see the results and she’s still doing fine.  We have more and more.  The group from Turkey, using this concept to manage advanced pancreatic cancer.  These are all stage four cancers, Lung, Pancreas, Colon, ovary, all stage four.  Using the same kind of therapy working the same way in all these different cancers.  Why? Because cancer is a singular disease of energy metabolism. Cancer is not a complicated disease, we have made it, as a species, we have made that disease complicated.  By chasing all these genes, that are largely irrelevant to the nature of the disease.  They need Glucose, and they need Glutamine.  You take away glucose and glutamine, you keep the patient happy,  healthy, and cancer free.  Now how long will these people remain?  They say it’s going to be resistant.  Resistant to what?  If you take away the two primary fuels there’s no way, it’s checkmate!

It is my firm belief, that if this becomes part of the standard of care, we will start to drop those numbers quite significantly.

 

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