The Primary Causes Of Cancer And The Truth About How Keto Affects Cancer with Chad Macias

Ari Whitten:  Yeah. Awesome. This is fascinating stuff. So I want to get into the metabolic theory of cancer and keto diets. So this has been written about by a few different people in recent years and kind of popularized this notion that, you know, for example, cancer feeds on sugar but not fat or ketones. And so if you go on a keto diet it kind of starves the cancer, you know, or reprograms the metabolism in a way that fights cancer. I know that you are pretty critical of some aspects of this. So what, why are you critical of this theory? What is wrong with it?

Chad Macias:  So there is a lot wrong with it, actually. It is pretty interesting to see how far this has come based off of what I could only describe as like, say bad science, is really what it comes down to. And I became really interested in this because it just became something I was very curious about. And cancer is always something I have wanted to study. My family has been affected by it. Most families have. My mom and aunt both had breast cancer. It has affected my wife as well. And so, you know, I kind of thought, you know, well maybe I can look at what is going on here. You know, I am a good thinker. Maybe I can help out here. I wouldn’t mind getting some education in this and seeing what I can do. I have done a lot in other fields I have worked in.

So that is what kind of pushed me down that path and was naturally guided to the keto for cancer discussion because it is so prevalent amongst the lay in social media. And then also in the research world, there is probably 400, you know, review papers on a ketogenic diet and cancer. And all 400 of them have specifically looked at rodent and cell culture data. So to get to where we are now, let me go back to the beginning so that people can understand really why I have been so critical. Because there has been a lot of very strong claims made about what the ketogenic diet can do for cancer and none of them are supported by any evidence in humans whatsoever. Not one of those claims. And so when you are making those kind of claims, and you and I both know that when they get filtered down to the layman, to the average person, what was said has been so diluted to begin with.

And if it is not based on accurate science, that is pretty dangerous. And so you can go into any chat room anywhere, in any type of social media, Instagram, Facebook, whatever it is, and you can find people giving each other advice on how to use a ketogenic diet to treat a family member or themselves with cancer. And that really is what kind of pushed me to say, “Well, hold on a second here. Let’s take a look at what is going on, because if that is the case, why isn’t that reflected in clinical trials?” And so when I look back to where this all started, around early 2000 you started seeing a series of cell culture papers being published that were looking at specifically glioblastoma. If I can remember correctly, I believe it is the U87 cell line, which was and still is pretty popular in studying glioblastoma.

And so what researchers were doing is they were allowing these glioblastoma brain cancer cells to adapt to the serum and the cell culture in that petri dish. And then they were investigating how they responded to glucose and fatty acids and proteins. And so they conducted these experiments and they were noticing, they were like, “Wow, you know, it really has an affinity for glucose and it doesn’t respond to fatty acids.” And so, you know, they continued doing more experiments. And this led to rodent studies. And that is pretty much where it stopped. And then the hysteria started. And then you had a lot of people who were fringe researchers in terms of, they are not oncologists and they are not medical doctors, right? So they don’t actually study cancer and they don’t actually treat patients, but they are studying ketogenic diets in rodents.

And that is where a majority of where this sensation that you see now on social media was started from, was a group of researchers who are what I would consider fringe in terms of cancer research. All well qualified, highly educated PhDs in biochemistry. And even some doctors that are not oncologists, but they are studying oncology and they are not working with human patients and they are drawing a lot of conclusions from their work. And it influenced everybody and it got really out of control. And so in looking at the clinical trials, I want to be at the forefront and the battleground of studying this. So I said, you know, I need to go get an education in cancer biology, which is where I am still currently doing that. I am still working towards my PhD in Molecular Oncology at [inaudible] University in Spain.

Started with my Master’s in Molecular Oncology at Center for Biomedical Studies also in Spain, which is the leading research facility for cancer research in the world. And I started asking questions. And when I looked at the clinical trials, which does exist in human patients and ketogenic diets, it is not improving progression free survival. And so why? Why is it not improving progression free survival there but it does in a majority of the rodent models, only a few of them does it not work, and in all of these cell culture studies? So I started looking at the cell culture studies to understand, well why is this showing up here but it doesn’t show up in human patients? Obviously there can be differences in between what happens in a petri dish and what happens in humans. But for the most part, what you see is fairly accurate of what you can loosely see biochemically within the biological individual.

And so when I looked at that, you start seeing all these papers that are recommending that you do not do cancer research when you allow the cells to adapt to the serum. So they lose their ability to differentiate, they lose their ability to be clonogenic to be tumorigenic. It changes their epigenetics. It prevents them from looking like the parent cell so they cannot recalculate anything that came from the actual original tumor. So it is a horrible place to examine what is going to happen with a substrate. And one thing that is very clear now when you look at cell culture studies that have specifically investigated this and the research studies that I will be sending you to put up on the page, I have got about 10 that specifically directly quote everything that I am telling you that say, “Do not conduct these types of experiments where you allow the cells to adapt to the serum.” They lose their fatty acid oxidation potential when you do that. So they cannot oxidize fatty acids when you allow them to adapt to a serum that has glucose or bovine or any of the other typical serums that you find. You can’t do it because you are going to get a picture that is incomplete where you think that they cannot use fatty acids but they actually can and sometimes at a higher rate.

Ari Whitten:  And so this is, just for anybody who got lost in the biochemistry that you are describing here, what you are basically saying is in the experimental model, you are going to draw the conclusion that these tumors are being starved on a low carb, you know, higher fat substrate. But in an actual living human being that would not occur and the tumors could maybe, it sounds like, easily adapt to burning fats or ketones for fuel. And maybe even, I don’t know, I don’t want to put words in your mouth, but maybe even preferentially use them for fuel or something to that effect.

Chad Macias:  Yes. Both of those can be true depending on the cancer. But to continue to draw the line from there, so that is exactly right. You have these cell culture, these petri dish experiments where they left glucose in there, the cells adapted to using glucose and not fat. When they introduced fatty acids, the cells couldn’t use them and they died. And so there is, it gives this illusion that that is what is going to happen in the individual. So they take those and they go to the rodent studies. Well, the same thing happens in a lot of the rodent studies. So that is going to bring about some pretty strong confirmation bias for researchers who are looking at this going, “Hey, wow, look, this is happening in the rodents, too.” So the rodent stuff, we will just keep very brief and very simple. Rodents have a basal metabolic rate that is seven to eight times higher than humans and a vastly, vastly, I’ll say it one more time, vastly different hepatic function compared to humans. It is a good model to rapidly induce obesity and look at changes in nutrition related to obesity influenced diseases, body mass and things like that. It is a great model to do that. It is a horrible model to investigate cancer when you are investigating how a high fat diet influences tumoral genesis. Horrible model to do that in. I see more value in jumping straight from cell culture to working with nonhuman primate like canine or monkeys and then humans then going to rodents because it will give off another illusion that you have this therapeutic intervention that you really don’t have because that environment will never exist in a human. So you get cell culture that went to rodent studies. The rodents happened to respond in a similar way that you saw in the cell culture.

There is a few different reasons also that there is problems with some of the rodent data that I will briefly mention. The group of researchers that was really spearheading this, Dominic D’Agostino, Tom Seyfried, those guys popularized this with a rodent model that they created themselves, the VMM3 model of metastasis. The problem with that is that it doesn’t have external validation. And for the listeners, what that means is that no other scientists or groups outside of these individuals use that model to study cancer and treat cancer with a ketogenic diet in that model. So the only ones to do it, they created it. And they started conducting these experiments in rodents and started drawing conclusions in humans saying, “Hey, you can use this in humans. It can be an adjunct, it might even replace chemo and radiation by itself,” which is crazy to say in a research study that you conducted on rodents. And so you have both rodents being an inappropriate place to investigate a high fat diet because of the changes in basal metabolic rate and the difference in hepatic function. And then you also have a group of researchers who are responsible for popularizing this diet and cancer intervention who used a rodent model that didn’t have external validation. So you have multiple different problems with the rodent side of the research as well.

Ari Whitten:  So I think I also heard, maybe I am interrupting your flow and you were going to get here, but,I think I also heard you say in another interview I listened to something to the effect of they actually miscited, you know, they made claims in their paper where they put citations next to it and the citations literally didn’t support the claims they were making.

Chad Macias:  Yeah. So, you know, I don’t want to throw too much mud because I try to get to a place where I can build bridges with people because I think we have a common goal to some extent. But certainly those research papers, there was references in there that were unrelated to the point. It wasn’t that the point was that it required a large amount of evidence. It was simply that when you started looking through some of the citations, they were like completely unrelated to what it needed to say. There was also a lot of things in the papers where they would make claims about biochemistry that, you know, “It is impossible to use fatty acids in brain cancer tumors because you don’t have the metabolic phenotype, you don’t have these biochemical milieu,” and all that stuff has been demonstrated to be false.

It was false when they said it. There was evidence to prove it was false when they said it. It has since been solidified as false with a lot of human data. So there was a lot of problems within their papers as well that you alluded to both with citations not being accurate and also an inaccurate description of what is actually happening within the tumor itself. Despite that they were describing what happens in rodents, they were still projecting that as that would be similar to what you would see in human patients. So if we fast forward to what happens in actual human patients, so let’s go to that data. We have talked about the problem with cell culture in rodents. So what happens in actual human patients? I actually have, there’s actually clinical trials that have been published.

A lot of people don’t realize that. I have got that data right here. So, the first study that was conducted by the Institute of Neurooncology Hospital at Frankfurt, it had 20 patients total, only 17 completed it. They had, they verified ketosis through urinary measures. The researchers were looking at what we call progression-free survival and overall survival. That is what matters in cancer. Progression-free survival is how long you can survive without the tumor itself, the cancer progressing any further with the treatment. Overall survival is achieved after five years of no progression from the cancer at all at the five year mark. That is considered overall survival. And so they, the researchers looked at overall survival and progression-free survival in a group of patients. They had different types of cancers. So you had glioblastoma, you had prostate, you had different types of cancers.

So the medium progression-free improvement was five weeks. None of the patients were, saw a change at six months where they weren’t progressing. So every single one of the patients had progressed by the six month mark. The average time before progression was about five weeks. So they did not achieve any significant progression-free survival in that group compared to what you would see with standard care. So the second study was with 12 patients at the Veterans Affair Hospital here in Pittsburgh. So they had patients that had prostate, melanoma, renal cell, pancreatic, colon, thyroid, head and neck and glioblastoma and lung cancer. Six patients discontinued treatment at four weeks due to the disease progressing. Two patients discontinued treatment at eight weeks, one due to a grade three weight loss, one due to disease progression. Three patients completed the 16 week trial.

Two of those patients died, one at 40 weeks one at 80 weeks with one patient reporting disease free at 131 weeks, which was the melanoma patient, which is, that type of melanoma was not terminal. So that was not unexpected. So you can see that when we look at the clinical trials that it has not led to any progression-free survival in the various forms of cancer that it has been investigated in.

Ari Whitten:  This, just to be clear, this was keto diets being investigated for these different types of…

Chad Macias:  What it was is it was a ketogenic diet used as what we call an adjunct to standard care. So the patients were still receiving chemo and radiation and they were introducing the ketogenic diet to try to improve the therapy itself. From a cancer biologist’s perspective, you use the ketogenic diet to sensitize the tumor to keto.

That is the hypothesis that has been put forward that it will sensitize it to the treatment because it is not going to have a fuel source. What we find when we actually started studying this a little bit closer is that we actually, Ari, found the complete opposite of that. And that is what makes this so frustrating is that the original cell cultures, not only were they conducted improperly, but it is actually the complete reverse when you do it properly. So when you actually investigate these things in cell culture, when you don’t allow the tumors to adapt to the serum and you introduce glucose or sugar and you introduce fat, fat is the preferred fuel source for glioblastoma, for brain cancer. And one of the things that… And the thing that I wanted to understand is why, again, why are these things happening? And if there is all this data in the cell culture and even with knowing why it is improper, you still want to find out what exactly is happening within a tumor.

How could the tumor use fat and how is it going to not be able to resist the treatment and how does it not resist the treatment? So I am asking all those questions at the same time. I study specifically glioblastoma. Myself, Tim Sharp and Brad Dieter are involved in a clinical trial at SUNY Upstate Medical Hospital University in New York where we are introducing a ketogenic diet as an adjunct for glioblastoma brain cancer patients. So we are actually trying to figure out ways for this to work and the reasons why it doesn’t work. And what that clinical trial has revealed to us is that when we start looking at the ways that a tumor can resist treatment, so why is a tumor terminal in this cancer but it is not in another cancer? And it is actually pretty simple. It comes down to antioxidant defense.

So you have chemo and you have radiation and they are trying to disrupt the DNA that the tumor is using to regenerate all the things it needs for fuel and biochemical needs. And it is also, we are using the keto which is trying to introduce cellular death and apoptosis, and it is inducing cytotoxicity in the cell which will lead to cell death. And the way that the tumor resists that is through antioxidant defense. So it wraps up glutathione production to resist the cytotoxicity that comes with chemo and radiation. So there’s a couple of noteworthy things that happen when we start looking at that really in depth, specifically in glioblastoma which is where a ketogenic diet has been prescribed the most is in brain cancer. So when you start looking at how does, how do brain cells produce glutathione to resist the chemo? And we start looking at it, it is actually produced through fatty acid oxidation. So fatty acids increase the ratio of NAD+ to NADH, and anytime you increase the ratio of NAD+ to NADH you are going to increase antioxidant production. And in fact, one of the chemotherapy drugs that is used specifically reduces NAD so that you can reduce that ratio and the antioxidant production. So fatty acids…

Ari Whitten:  Just to be clear, this process that you are talking about, I think it also involves things like sertuins and Nrf2 pathway. This process is profoundly beneficial to ramp this process up in normal healthy cells. But you are talking about when it is happening, when it is being ramped up, and the internal antioxidant defense system is being bolstered in tumor cells, that becomes their defense against things like chemo or radiation.

Chad Macias:  Yes. Correct. And so there is a couple of kind of large indicators of what is going on that a lot of these researchers seem to ignore. And so when you look at patients who are on chemo and radiation for any type of cancer, it doesn’t have to be brain cancer, one thing you notice is that regardless of the metabolic phenotype of the tumor… So some tumors do prefer to use sugar and/or glucose. That is true. There are tumors that will prefer to use sugar and glucose and as they change throughout tumor progression, that changes and they go to using more proteins. Or, like pancreatic cancer has an upregulation of autophagy. And there is all these just random different things for each cancers. But what you start to see is that these different types of tumors resist the therapies by switching over to oxidative phosphorylation.

So they all start using fatty acid as their main fuel source when you try to kill them. All of them, every one of these tumors that you find, the cells within them will start going to ox-phos to fight against the stress that is created by the treatment. And the reason that it can do that is, again, because fatty acids can support glutathione production in the mitochondria and the cytosol, and it was always thought that it was glucose through the pentose phosphate pathway that that is what was happening. But in fact, that is not the case. It is actually happening through fatty acid oxidation that it is increasing the NAD/NADH ratio.

Ari Whitten:  Yeah. So the bottom line…

Chad Macias:  So basically fatty acids and ketones can increase the NAD+ to NADH ratio, which will increase glutathione production and help the tumor resist the chemo and radiation. And when I start looking at, there are survivors which we call extreme survivors of glioblastomas and there’s a couple of survivors that have utilized a ketogenic diet. So it is like, okay, so if this is the case and I am so sure of myself, then how did this person survive despite using a ketogenic diet? So that is where IDH1 mutation comes in. So there’s different types of mutations that happen within glioblastomas.

Chad Macias:  There is several and that can actually define the type of brain tumor it is. And one of them is the IDH1/IDH2 mutation. And when we started to look at that a little bit closer, I had a feeling that we were going to find that fatty acid oxidation is down regulated in those with the IDH1 mutation and sure enough it is. So in the people that have an IDH1 mutation, they don’t have the ability to oxidize fatty acids to improve that NAD/NADH ratio and improve…

Ari Whitten:  This is specifically in the tumor cells or throughout all the cells.

Chad Macias:  Well, this would be specifically in the brain tumor cells.

Ari Whitten:  Interesting. And so a lot of this stuff is actually a little more specific to brain cancer in terms of like the glutathione production in glial brain cells is really where this plays out and it may play out in other areas.

Chad Macias:  I haven’t studied that in other cancers, but I have a feeling it will, not in all, but most will. It will be similar in that glutathione production is better supported through fatty acids. And that is clear by the fact that all tumors switch to oxidative phosphorylation when you introduce chemo and radiation. The second you introduce chemo and radiation, the tumor that had previously been living on glucose will immediately switch over to oxidative phosphorylation and start using fatty acids as its fuel source, also as its carbon source. So, tumors don’t just take glucose and fatty acids for fuel. They will break them down so they can get the carbon [inaudible] from it and they can take it and use it for building blocks in rapid proliferation. So that is another thing. People have a misconception that, you know, that glucose and fatty acids are only a fuel source and that you can starve the tumor.

They are not just used as a fuel source. And anytime you try to starve one of those fuel sources, the tumor will literally just adapt. It is such a reductionist approach that is totally ignorant of how intelligent cancer operates on. I just want to bang my head on the wall when people suggest stuff like that.

Ari Whitten:  Suggest like basically that cancer feeds on sugar and if you eat a low carb ketogenic diet you are starving the cancer. That level of reduction is what you are talking about that makes you want to bang your head against the wall.

Chad Macias:  Yeah, that is just ridiculous. You don’t think that we would be doing that as cancer researchers to help these patients live? Like, I mean it is just asinine to think that something so simplistic we wouldn’t just do it. You know, there is a lot of misconceptions about what happens in cancer research and you always hear Big Pharma and their influence.

Big Pharma is the reason why our rates of cancer death have dropped significantly. Even though chemo has its own set of problems that come along with it, it saves a ton of lives. And standard care is hands down the best way to go about it. If my children or my wife, as we are currently dealing with a cancer in the family, I will highly recommend standard care across the board if immunotherapy or a really attractive clinical trial is not available. It is hands down the best way to do things. And to think that you could still simplistically do something that we wouldn’t just do on our own accord. There’s no, Big Pharma doesn’t fund… The majority of cancer research is funded by the NIH or the university itself that conducts it. Big Pharma puts very little money into cancer research unless it is for the drug they are developing. So, and there hasn’t been very many drugs developed in the last 20 years for chemo or for radiotherapy, which is now majority done through laser, anyway.

Ari Whitten:  Got you. One more little digression, which is the Gerson diet and the, you know, kind of the vegan approach to cancer. There’s a little bit of a battle even among the people who think, you know, standard care, chemo radiation should be avoided. There is an internal battle where even within those people, there is a division where some people are more pro-keto and other people are more anti-keto, pro-vegan diet. Do you have any thoughts on that debate at all?

Chad Macias:  Yeah, sure, I do. I think that anybody arguing for the use of the ketogenic diet as an adjunct outside of a clinical trial setting doesn’t know what they are talking about. We don’t have any evidence in humans that this can improve progression-free survival. So I don’t understand why people continue to draw conclusions from studies that are not in humans to treat humans. The human data suggests it is not effective. So I would say that that is, they definitely should not be voicing their opinion if that is what their opinion is because it is not validated by evidence. So in looking at the side, the vegan or the juicing and the coffee enema side of things. So it sounds attractive and it seems intrinsic that you could be healthier by doing those things. The problem is the evidence is just not there.

I personally have investigated it. I have contacted the NIH about it. There has been research studies published on the Gerson methods and when researchers at the NIH and other cancer biologists looked at their data independently and asked for five year follow up from their cancer patients, it did not exist because they did not follow up with a single patient. So when these researchers track down all of these patients at five years, the group of 50 patients that they chose to track down, all but one was dead and the one that was alive still had cancer and died within a year. So the evidence would suggest they are not treating cancer at all. The evidence would suggest they are sloppily helping people with a method that I am not sure that has any value. There was probably a dozen reported cases of death from their methods from both the enemas gone wrong and also the use of raw liver led to a number of deaths here in San Diego that are all… I will happily also send those to you. All of this stuff is published in peer review, which is a wonderful. So there is no evidence for that.

Now with that being said, I know of a few different clinics where people that I have personally helped through the cancer journey have went where they used a combination of Gerson like method along with low dose chemo and a few other natural methods with success that I verified through MRI and pet scan at an oncology hospital that is well-respected here in the U S. So I do see value in using methods like that when they are combined with standard care. But when you have groups like the Gerson Hospital and other institutes that are using those as their standard care, I think it is a recipe to die and to die quickly. I don’t see any value in that stuff at all.