Transcription
Well, I want to thank Emily and Bob and Greg for the kind invitation to come here and present some of our recent, uh, historical information on cancer as a metabolic disease. Um, I don't want this to be too loud; is it too loud? Am I blowing somebody's eardrum out here or anything? No? Okay, um, yeah, so, uh, cancer is a mitochondrial metabolic disease, uh, is what I'll be speaking about, uh, this afternoon.
And, um, I have a couple of, uh, quotes that will introduce what we need to know about. I think Greg hit upon one of these in his presentation. Um, but when we talk about, and what Dr. Palmer was speaking about, uh, we have certain mindsets in people related to some of these quotes here from Carl Sagan. You know, “We live in a society driven by science and technology, and most people have no clue what's going on.”
Um, Tolstoy: “The most difficult subjects can be explained to the most slow-witted man if he has not formed any idea of them already, but the simplest thing cannot be made clear to the most intelligent man if he's firmly persuaded in what he knows already without a shadow of a doubt.”
We have these problems of assimilation bias or confirmation bias from Francis Bacon, uh, the originator of the scientific method: “Human understanding, uh, when it has once adopted an opinion, draws all things else to support and agree with it.”
And, of course, in our area, uh, follow the money. Upton Sinclair: “It's difficult to get a man to understand something when his salary depends on him not understanding it.” This is, uh, really all of these together, uh, represent, uh, some of the challenges, uh, that we have that speak to your philosophy of science in one way or another. Um, but what we do is, um, we document every year, uh, the, the, uh, American Cancer Society. One of their major functions is to, uh, log the dead, uh, basically, uh, new cases, deaths per year, deaths per day, and you can see it's always increasing, um, to some degree, uh, more new cases.
Um, and, and, you know, we're getting almost 1,700 people a day in the United States dying from cancer. Uh, and if you divide that number by 24, it comes out to about 70 people per hour, okay? This is not an insignificant—this is an epidemic.
We keep throwing massive amounts of money into these problems—billions and billions of dollars, both from the federal government and from private foundations. You know, the pink ribbon campaigns, you hear all about them. People just mindlessly run out and throw money at a problem; they have no clue where the money is going. There seems to be no accountability, either in the federal government or for the private foundations.
It just seems to be a year-in, year-out ritual of throwing money at a problem with the expectation that something will be different, and generally, it doesn’t. What I do is I check the scientific advisory boards of the individual foundations that support it, and then you can know, uh, why we're not making any progress.
This is a lot of words—cancer statistics from 2024. What they want to say here is that we are making major progress in reducing the death from cancer. I spoke to someone the other day who said, “This is the most exciting time for cancer,” and all this. And I said, “What about all the dead people?” They said, “Yeah, well, that's an unfortunate problem.”
Um, but, uh, but one of the things they tell us, uh, about all the progress we're making—in the early 1990s, uh, there was this anti-smoking campaign, uh, where secondhand smoke was bothering people, right? You sit next to this guy, “Oh, you can’t.”
So it was societal peer pressure on people that smoking was unacceptable. You know, years ago when I would go to scientific meetings, you'd have to wave the smoke away—you couldn’t even see the slides! Right? Scientists were all puffing away; everybody’s puffing away. Half the restaurant was smoking, half was non-smoking.
Now if they catch you smoking, they have a team come out and beat you half to death! So as a result of that, we’ve prevented a lot of cancer deaths, okay? So the red line is all the people that would have died had we not stopped smoking.
Alright, so if we didn’t stop smoking, we would have had all these dead people, but we’re still on a trajectory of increase. So the biggest reduction in cancer has been a prevention one, a behavior—personal behavior one—not from what we think of with all the advertisements we hear on television every night about how wonderful it is. They show you some smiling guy riding a bike, and then they give you 15 different ways the treatment could kill you.
The problem is, it's personal choice that does a lot to reduce this. So we're going to talk about cancer. What is cancer? It’s just disregulated cell growth. People always say, “What is cancer?” It’s cell division out of control. Um, is this disorder caused by genetic mutations? And we're going to talk about that.
Uh, or is it caused by chronic insufficient respiration, coupled to compensatory fermentation, or what we refer to as substrate-level phosphorylation? Now, a little bit about theories in science: a scientific theory is simply an attempt to explain the facts. The data, the facts—reality is based on replicated facts, whereas interpretation of the facts is based on a credible theory.
You collect a lot of data, and people have different ways to interpret it. And if everyone is interpreting it in a similar way, then we have a theory. We can test that. Credible theories move science forward, whereas flawed theories can stall scientific progress.
Now let’s look at some of these in historical perspective. The heliocentric theory could explain better the movements of celestial bodies than could the geocentric theory. Now, for 1,800 years, the ideas of Aristotle and Claudius Ptolemy, uh, focused on how to explain the movements of the planets when the Earth is immovable and stable.
We see the moon, we see the sun, we see the planets, and then we see the stars, which are actually in a separate sphere. It was a series of mathematical epicycles, uh, deference, where the planet is moving in one way and then all of a sudden decides to turn and go in a different way. There was a lot of mess for 1,800 years.
Then Nicholas Copernicus, up on the top, uh, struggled with all the epicycles and the mathematical problems with the celestial bodies. He said, “Maybe if we rearrange the organization of the celestial bodies—if we put the sun in the center and make the Earth simply another planet—maybe we can better account for the predictability of where these planets are supposed to be at the time they’re supposed to be there.”
Again, we find predictability that was far more accurate than previously thought. Of course, the next guy, Johannes Kepler, understood that they were not just perfect circles but ellipses. He jumped all over that—he knew exactly what Copernicus was saying. Of course, Galileo developed the telescope to confirm the moons of Jupiter and also the angles of the planets' movement.
He was very excited. Of course, he was put under house arrest by the Catholic Church. You were threatening the power establishment at that time, which was the Catholic Church, the seat of all knowledge and predictability.
Now, the poor guy on the bottom—does anybody know who that guy is? The lowest guy here? Anybody know who that is? Nobody? Giordano Bruno—have you ever heard of Bruno? Bruno was a cleric in the Catholic Church, and he was a strong supporter of Copernicus. He ran around and told everybody that Copernicus was right—the Earth is not the center of the universe, the sun is.
That didn’t go over well. They stripped him naked, held him upside down, and burned him alive in a plaza in Rome. He’s considered the martyr of science—Giordano Bruno, you should all know. Galileo got away with house arrest, but poor Bruno was burned to death. Why? He was challenging the power structure at the time.
But there was one thing that Bruno said that really put the flame to the torch here: he said, "There might be life on another planet." Oh, that was it—he was gone, forget about his ass, he was finished, and that was the end of Bruno.
But the key is, it started what we call the Copernican Revolution, and the Renaissance of science in Europe is the result of this. Then we have the germ theory, which could explain better the origin of contagious diseases than the bad air (miasma) theory. The miasma theory came from Galen, a Greek-Roman physician, and his ideas about disease permeated all the way into the 1800s.
It was Louis Pasteur who clearly showed with his experimentation that germs actually cause disease, not bad air, not miasma. He was vilified by the French medical aristocracy at the time because they said, “He doesn’t have an MD degree; therefore, we can’t believe anything he says—he’s only a PhD!” But he turned out to be right—the MDs were not right.
And then, of course, there’s the Darwin-Wallace theory of evolution by natural selection, which could explain better the origin of species than the theory of special creation. Those little numbers on the top there are the descendants of original ancestors. Each one of those horizontal lines could represent millions of years, hundreds of thousands of years.
You can see all the extinctions that have occurred in the organization of biological plants and animals over time. I have a whole chapter in my book on cancer—nothing in cancer biology can make sense except in the light of evolution. So we incorporate evolutionary theory into our design of therapies that we use in the lab.
And thank you to Chris Palmer for at least identifying what the mitochondria are. It’s actually a spaghetti network inside the cell. These diagrams you see in textbooks make them look like little beans, but they’re actually a spaghetti network—they fuse, they divide, and they have a very active participation in the energetics and vitality of the cell.
So, can the mitochondrial metabolic theory explain better the origin and management of cancer than the somatic mutation theory? This is the next big transformation in medicine. Which of these theories is correct? We're going to dive into this and let you, as rational thinkers, come to your own decision as to what you think might be what we're dealing with here.
Does cancer arise from nuclear somatic mutations, or from chronic mitochondrial damage with compensatory fermentation? There's a two-step here: you have to have the chronic damage, and you have to have protracted compensatory fermentation, or what we refer to in our lab as substrate-level phosphorylation. Fortunately, I have my research crew back here—if I screw up with one thing, they will attack me! Not you good folks—those guys. Bob is there with the rest of them, so I have to be careful.
So, we're going to talk about these concepts. We’re looking at two organelles here—the mitochondrion and the nucleus. The somatic mutation theory of cancer says that disregulated cell growth is due to mutations in the nucleus that cause the cell to become disregulated or grow out of control. I will present evidence that challenges that.
We put up this paper—this is by Hanahan and Weinberg. They’re down here—Robert Weinberg is at MIT. This is one of the most highly cited papers in all of biology—cited by 75,000 times—Hallmarks of Cancer: The Next Generation, a dogmatic view, an irrefutable truth, a silent assumption, if you will: cancer is a genetic disease. And cancer cells carry the oncogenic and tumor suppressor mutations that define cancer as a genetic disease.
Page 661 in the paper—you can read it if you have the paper; if not, I can send it to you. Okay, so this concept has now permeated all of the textbooks of biology, biochemistry, and cell biology. All the medical students, when they get their first year of training and they do biochemistry or whatever, they're talking about cancer as a genetic disease driven by different kinds of mutations that we're going to look at.
Not only that, it's also supported by the National Cancer Institute—our government’s cancer website, the National Cancer Institute. What it says right there: "Cancer is a genetic disease; that is, it is caused by changes to genes that control the way our cells function, especially how they grow and divide.” Down at the bottom there: "Cancer is caused by certain changes to genes."
This is confirmation bias. What this means is, in terms of Francis Bacon’s assimilation bias and confirmation bias, the whole field says cancer has to be a genetic disease because the NCI says it is, and everybody else thinks it is—not everybody, but a lot of people.
So let's look at this somatic mutation theory. If you’re going to understand what the current theory of cancer is, because ultimately, if you think you understand what the disease is, you should be able to strategize therapies that manage it. And you just saw all the dead people piling up—something's not right.
So, we have mutations in tumor suppressor genes and proto-oncogenes leading to cell division out of control. So we look further at this, and we see that a tumor suppressor gene is a normal product of some gene, a protein of a gene in our genome, and it keeps normal cells in a growth-regulated state. A mutation happens in that gene, and you get disregulated cell growth. This is called a tumor suppressor.
These are tumor suppressors. But in addition to tumor suppressors, we also have these things called proto-oncogenes. A proto-oncogene is a normal gene in our body, but if it gets a mutation, some sort of mutation—there are several different kinds of genetic changes—you can have a mutation in the normal proto-oncogene, and that causes an oncogene, which makes the cells grow faster.
You can have a mutation in there, or you can have extra copies, multiple copies of this proto-oncogene, leading to normal growth-stimulating proteins in excess, or you can have the gene move around the genome and find itself next to a different kind of promoter, forcing the product to be in excess, leading to disregulated cell growth.
So we have the tumor suppressor genes, proto-oncogene, and oncogene, and these kinds of things, and this is all part of the somatic mutation theory—the current dogmatic view of what we think cancer happens to be.
So this is Dr. Vogelstein from Johns Hopkins. He says, “We now know precisely what causes cancer: a sequential series of alterations in well-defined"—and remember this term—"driver genes.” Not all the genes we found—oh my God, there are some that don't do anything: passengers, valleys, hills, all this kind of stuff. Drivers are the key.
So the key to managing cancer is going to be to target the driver genes that are causing the disregulated growth in a tumor in your body, okay, or causing a particular population of cells to become disregulated. All these things happen.
Now, here we are today. Individuals' cancer cells are genetically tested for personalized therapy. You hear about all this precision medicine, personalized therapy, all this kind of stuff. Breast cancer cells are being examined to see if they possess extra copies of a particular gene. There was a company down here in Kendall Square, Boston, that was bought out for $2.4 billion dollars.
It's a company that looks at tissue from cancer patients and looks at hundreds of different kinds of mutations. And you get this nice readout, “Oh gee, look at all the mutations I have.” They look at that and say, "We can give you a short list for $4,000, but if you really want the Cadillac list, you can pay another $7,500, and we'll give you thousands of different mutations."
And you say, “Wow, what are we going to do with all this information?” But anyway, the information keeps a lot of people employed, looking at screens and things like this. But you also have the observer effect, which is the Heisenberg uncertainty principle applied in human tissue. By looking at it and disturbing it, you have changed it.
So what you're looking at may no longer be what's happening inside your breast or colon or whatever, that tumor from which you're taking the biopsy. Now, again, we already heard about Ioannidis and his papers before. This is a paper from his group showing that the new cancer drugs aren't working.
The bottom line is they looked at 92 drugs from 2000 to 2016, and what's very interesting about these therapies is, if you look at the tumors of the patients that were treated with these various kinds of precision drugs or whatever you want to call them, it looked like the tumors were—wow, the tumors were really responding well. It's unbelievable! But the people don’t live any longer.
Very little—like two and a half months longer. What I understand is that the Food and Drug Administration determines whether a new drug should be given to human beings based on progression-free survival. That means what does the drug look like it’s doing to the tumor? And if there is some modicum of overall survival benefit, well that’s great, but we really should be looking at: does the drug keep you alive far longer than any of these other drugs? And they don’t look at that. That’s not part of what they're looking at.
Now, evidence challenges the somatic mutation theory, and whenever you challenge the dogma, you end up like Bruno, right? So you’ve got to be careful—people don’t want to look at it, they don’t want to talk about it, they don’t want to hear about it. We like to quote Einstein—we're all big on whatever Einstein had to say: “No amount of experimentation can prove me right, but a single experiment can prove me wrong.”
Well, let me show you stuff that should have proved the somatic mutation theory hopelessly wrong. Here we have Theodore Boveri, in 1914, who wrote this paper—a purely speculative paper—where he thought that cancer might have something to do with abnormal chromosomal behavior, movement of chromosomes. He came to that revelation looking at sea urchins, and he even said, "I have no clue how sea urchins are related to cancer."
Even his friends in cancer said, "You know, Theodore, I think you’re out to lunch." He said, "I’m probably totally wrong, and I want to apologize to the entire cancer community because I’m wrong, I have no knowledge, I’m ignorant.” And now we’ve anointed him as the father of the somatic mutation theory. So go figure.
Now, we’re looking at some cancers that have no somatic mutations. Greenman showed this, Baker, Parsons, and everyone—those are big papers. So you say, “Wow, look at that!” They found 30% of breast tumors using a very powerful genomic sequencing analysis had no mutations, yet some other breast cancers had thousands and thousands of mutations.
I was looking for how you explain that in your somatic mutation theory. Nothing. The same with Parsons—they couldn't find, in one of the glioblastoma papers, patients that had no mutations in any of the major signaling cascades. Well, interesting. Now, new data are showing us that these cancer driver genes are abundant in all of our cells that never become cancerous.
It’s unbelievable! So if we took samples from all of us, we’re loaded with driver mutations. You go down to Dana-Farber, and they say, “Oh, we’re going to start radiating and poisoning you—you’ve got all these mutations." And you say, “Well, what’s wrong with me? I’m perfectly healthy.” “Oh no, you’ve got the driver mutations.”
This can also account, in part, for why when you give immunotherapies to some people, the immunotherapy sometimes kills you before the cancer does. The problem is, of course—and Martin Karis pointed this out—okay, we’re going to target precisely that mutation, precisely that epitope, but oh—my kidney also has that. Well, we’re going to take your kidney out along with the cancer. What’s going to kill you faster?
We’ve got what's called hyper-progressive disease, and it’s a well-known phenomenon in cancer. Some cancers don’t cause mutations, like asbestos, right? Asbestos—the rarity of cancer in Aboriginal tribes. People who live according to their traditional ways, like these Africans and Inuits from the Arctic—the British were shocked. Albert Schweitzer couldn’t figure it out.
He looked at 10,000 Africans through his lens—nobody had cancer. It was strikingly different from the Europeans. The Inuits—I went to medical school at Thunder Bay, Canada, and they service the Inuits. They’re massively unhealthy—obesity, diabetes, dementia, all kinds of things. And yet, 100-150 years ago, they were some of the healthiest people on the planet.
All they did was eat meat and fat—they weren't eating vegetables or fruits or much else, except seasonally. It’s very interesting: when the western diet and lifestyle enter your population, brace yourselves—you’re going to have all kinds of chronic diseases. And of course, our closest biological relative, the chimpanzee, which is 98% similar to us in gene and protein sequence, has never had a documented case of breast cancer in a female chimpanzee.
Breast cancer is a big problem in humans, but there’s a stark difference here. The chimp is living according to its diet and lifestyle, whether it’s in the forest, or at Franklin Zoo down here in Boston, or in the San Diego Zoo. I was at the San Diego Zoo, and I said to the vet, “Why don’t you get a big box of jelly donuts for these things? I’m sure they’d like it.” “Oh yeah, they’d like it, but it’s very unhealthy.”
I said, “Well, I’m standing here eating a jelly donut!” You know, we’re not allowed to do these kinds of experiments on chimps—it’s called animal cruelty. Can you believe it? So, I checked—go down there yourself and ask the vet.
Now, the nail in the coffin came from what I simply did: I went out and looked at all these studies that transplanted the mitochondria or the nucleus from tumor cells into normal cells and moved both nucleus and mitochondria back and forth between different cells. I didn’t do these experiments—what I did, for the very first time, is reinterpret the data that’s already there in a different light.
And I published this paper—I actually did it in my book in 2012, and then this was in 2015. It’s got over 100,000 views and downloads right now. This is the very simplistic summary of dozens and dozens of replicated experiments. Replicated. So green cells get other green cells, normal cells get normal cells—the nucleus is healthy, the mitochondria structure and function are healthy, and they produce cells that are regulated in their growth during normal turnover.
Red cells are tumor cells. Tumor cells beget tumor cells, and tumor cells have genetic defects—that is true. Some don’t, but many do. They also have abnormalities in number, structure, and function of the mitochondria. So what is causing the disregulated growth? Is it the mutations in the nucleus, or is it something in the cytoplasm—abnormalities in the number, structure, and function of mitochondria?
When the red nucleus from the red cell is placed in the green cytoplasm—this was done by Israel and Schafer, in vitro and in vivo—they got regulated growth, which left them scratching their heads. Then they took the nucleus from the normal cell and put it in the cytoplasm of the tumor cell, and they got disregulated growth. This is just the opposite of what you would have expected if driver genes were controlling disregulated cell growth.
Newer experiments now—if you take the green mitochondria and purify them and put them into the red cytoplasm, you get regulated growth. If you take abnormal mitochondria and put them into indolent cells, they become explosive. Clearly, what nature is telling us is that this is a disorder driven by mitochondrial dysfunction, not by nuclear mutations.
If somatic mutations are not the origin of cancer, then how do cancer cells arise? We need to know the answer to this, and this goes back to the work of Otto Warburg, the German scientist. There’s a fascinating book written by Sam Apple. Warburg was a Jewish scientist whom Hitler spared because Hitler feared cancer and hoped Warburg would cure cancer someday.
What Warburg actually found is that cancer arises from chronic damage to cellular respiration. We’re all breathing, getting our oxygen through oxidative phosphorylation—this is what we're working on. Substrate-level phosphorylation is a non-oxidative form of energy. You move a phosphate group from an organic molecule onto ADP to get ATP—it’s different from oxidative phosphorylation. It's an ancient pathway.
These are the ways cells got energy before oxygen came into the atmosphere two and a half billion years ago. Cancer cells upregulate these ancient substrate-level phosphorylation pathways. Cancer cells continue to ferment glucose in the presence of oxygen—aerobic fermentation shouldn’t happen.
This is called the Warburg effect. There’s a lot of confusion about the Warburg effect. Our big contribution to the cancer field is that we now know that amino acid glutamine—the most abundant amino acid in our bloodstream—can also be fermented in cancer cells. This is different than what everybody thought—they thought it was respired.
Derek Lee, sitting here, has some of the strongest evidence of that. We’re working with Christos Opoulos at Semmelweis University in Budapest, Hungary. He’s the world leader on substrate-level phosphorylation in the mitochondria, and we’re now doing research. Warburg didn’t know about this.
They threw Warburg under the bus when Watson and Crick discovered the gene. Everyone said, “Oh, these tumor cells are full of mutations.” But Warburg was essentially right—he just didn’t have all the parts of the puzzle. We've now connected the dots and shown that he was essentially correct. Enhanced fermentation is the signature malady of all cancer cells.
If you look at a tumor and you go down and get the woman to look at all the different mutations, every cell in that tumor has a different constellation of genetic mutations—they’re not all the same. This breast tumor, that breast tumor—they’re all different from each other. Nobody has the same mutations, even within the same tumor—all the cells are different from each other.
But one thing is common to all of those cells: they are fermenting. They’re getting their energy from a non-oxidative source. So the key to managing cancer is to take away the fermentation fuels. I mean, it’s not complicated, and you're going to come to realize that.
So what’s the evidence? Are you sure about that? Well, let’s look under the electron microscope because that’s where you can really see mitochondrial structure. You can isolate them and look at their function. So, the cells—those nice, beautiful stripes—they are the cristae. They contain the proteins and lipids that drive the electron transport chain.
Chris showed a picture of the electron transport chain. That’s a healthy mitochondrion. The one on the right—that’s a glioblastoma mitochondrion, deadly brain cancer. You can see the cristae are missing—it’s called "cristalysis." Structure determines function. It’s an evolutionary conserved concept—if the structure of the organelle is abnormal, the function of that organelle will be abnormal.
Now, what about breast cancer? On the right, the healthy cells, there are normal breast cells—nice, beautiful stripes of the cristae. We brute-forced these mitochondria—we took out all the lipids, analyzed everything in incredible molecular detail. The cancer cells have a very abnormal lipidome, and you can see the vacuoles in the breast—the spots there are vacuoles.
Colorectal cancer mitochondria—these are empty of cristae. Structure determines function. Now, what I did is I went back and looked at all human cancers that we have studied over the years, decades from the 60s, 70s, 80s. In the early days of electron microscopy development, people were looking at everything and recording what they saw.
So I just went back and said, “Look at this, guys—they’re seeing all these different cancers with abnormal structure and function in the mitochondria.” All of it represents over 90%—bladder, breast, colorectal, gliomas, blood cancers, liver, melanomas, osteosarcomas, pancreas, prostate—they’re all similar. They all have problems—abnormalities in the number, structure, and function of the mitochondria.
In our most recent study with Dr. Tea, we put that together. When you can’t respire, lipids can be deadly because they’ll create reactive oxygen species (ROS) and potentially kill the cell. So what the cell does is evacuate them—they put the lipids in these lipid droplets (LD). That’s a sign that the mitochondria aren’t working because if they were, they’d use those fatty acids. They’d explode from the ROS.
So, to protect the cell from death, they store them in these droplets. We went through all the major cancers—colorectal, breast, blood cancers—they’re all storing lipid droplets. It’s a marker for deficient oxidative phosphorylation, meaning that those cells need to ferment. What do they ferment? Glucose and glutamine. Right? How come nobody’s targeting the glucose and glutamine? Too simple. Very simple. Can't do simple things.
So when we look at energy metabolism in normal cells, here’s a very simple overview. Glycolysis—called the Embden-Meyerhof-Parnas pathway—is documented well. Glucose is metabolized through a 10-step process to pyruvate. Pyruvate goes into the Krebs cycle, fully oxidized, producing reducing equivalents like NADH and FADH2, which deliver their electrons to the electron transport chain, and we get tremendous amounts of energy with waste products of CO2 and water.
CO2 and water come right out. We also get a little energy from substrate-level phosphorylation. These are the ancient pathways that existed for energy metabolism before oxygen came into the atmosphere. The cancer cell, though, you see the shift. You get a lot of energy now from these ancient fermentation pathways—called substrate-level phosphorylation—and you can see that.
We’re not really sure of the percentage—that’s one of the debating points where we’re not sure. But energy through oxidative phosphorylation is neither necessary nor sufficient for driving disregulated cell growth. Glucose and glutamine fermentation in the cytosol and mitochondrial substrate-level phosphorylation are necessary and sufficient for driving disregulated cell growth.
I don’t want to bore you with these. We love these things, you know—we could spend hours looking at this stuff. But you can see glycolysis and glutaminolysis—those are the two driving pathways that provide the energy for disregulated cell growth and the metabolites needed for new growing cells. You see these starbursts here—glutamine, glutaminolysis, glycolysis, and energy.
These cancer cells are, in fact, taking in oxygen, okay, but they’re blowing out reactive oxygen species (ROS) that are carcinogenic and mutagenic. So, we’re not getting very much energy from oxidative phosphorylation. We’re getting more energy from substrate-level phosphorylation, with succinic acid and lactic acid as waste products—not CO2 and water, but succinic acid and lactic acid.
And we’ve measured that—Derek’s measured that. Now, this is Derek’s gift to mankind. He put a lot of energy into this. Derek, stand up there! Let people see who you are! There he is, right there. So he put a lot of energy into this, and we thought about how we’re driving disregulated cell growth through using glucose and glutamine as fermentable fuels.
Derek came up with the idea that this is a high-throughput system. These cancer cells are sucking down these two fuels in enormous amounts relative to normal cells, and they’re blowing out lactic acid and succinic acid into the microenvironment.
You know, one of the biggest things in oncology is: “My immunotherapies don’t work. My chemo doesn’t work. My radiation doesn’t work.” There’s so much acidification in the microenvironment, it’s blocking all these things from working. Where’s the crisis? Where’s it coming from? Glucose and glutamine.
If I take away glucose and glutamine, these things now become vulnerable. But nobody’s doing that, right? Nobody’s doing that. But anyway, Derek showed all the linkages—these two powerful pathways are feeding off of each other in a synergistic way, driving the disregulated cell growth and the metabolites needed to make new cancer cells.
And then we put this together. Okay, we’ve got the beautiful normal mitochondria on the left, and over time, chronic disruption of oxidative phosphorylation leads to ghost mitochondria. The Delta G prime of ATP—this is the key that you have to know—that is underlying the energy efficiency.
So, we’re keeping the energy efficiency, but we’re shifting. The green line goes down—that’s oxidative phosphorylation. Then there’s a protracted increase in substrate-level phosphorylation. To bring Einstein back again, substrate-level phosphorylation is linked to malignancy as strongly as gravity is linked to the red shift.
Anybody know what Einstein's red shift is? The pull of gravity on photons? It’s an unbelievable thing. That’s how strong the linkages are. So we can now put all the parts of the puzzle together again. The common pathophysiological mechanism for cancer is damage to the mitochondria.
That damage can come from radiation, chemical carcinogens, intermittent hypoxia, systemic inflammation, rare inherited mutations, oncogenic viruses, older age. Every one of these things impacts negatively on the structure and function of the mitochondria, producing reactive oxygen species (ROS), which are carcinogenic and mutagenic.
So, most of the mutations that we see in the nucleus of the tumor cell are downstream effects of mitochondrial damage and dysfunction. Yet we’re chasing tails—we’re not chasing the origin. So ROS go on, now the oncogenes turn on, and their floodgates—those are the high-throughput pathways of glycolysis and glutaminolysis—are driven because the mitochondria are suffering.
So how is the cell going to survive? It has to get an alternative energy. The alternative energy is substrate-level phosphorylation, driven by glucose and glutamine. Now, we can take all of the hallmarks of cancer produced by Robert Weinberg and Hanahan and link every one of those back to dysfunctional failing mitochondria.
Now, there's a book—Sid Mukherjee wrote The Emperor of All Maladies. Mukherjee struggles in the book: “I don't understand what's the common pathophysiological mechanism. I don't understand.” And the end of the book is very bleak. Read it—it’s very depressing.
I said, “For Christ’s sake, didn’t you read some of our papers? You wouldn’t have been so depressed. You should be on a ketogenic diet or something!” Now, if most cancer cells obtain energy through fermentation, what therapies might be effective for managing cancer?
Well, one approach is to target those fermentable fuels. Now, I’m going to show you the evidence. I’m going to show you the power of predictability. As Greg would say, “If you're on the right path, you should be able to predict something,” right? So, here’s the strategy: metabolic management of cancer, following changes in plasma glucose and ketones.
Let’s lower the glucose—water-only fasting. I’m going to talk about that in a minute. Calorie restriction, restricted ketogenic diets, and then raise ketone levels because it’s the glucose that’s driving the disregulated growth. Now we’re going to give them fatty acids and ketones to choke on, right? And not only that, it’ll make the rest of your cells healthy.
We’re going to increase the Delta G prime of ATP hydrolysis. This is the key to why ketones are effective—they increase your Delta G prime. Now, look at this: the ad libitum mouse is given all he likes—let him eat as much as he wants. The other group is the calorie-restricted group, restricted by 40%—calorie restriction three days post-inoculum.
And you can see we got a huge reduction in the size of that tumor. It's obvious. People say, “Wow, all I have to do is cut my calories back by 40%?” No, wrong. Forty percent in a mouse is water-only fasting. Do you have another option? There’s something else you can do?
You know, they don't want to water-only fast. You can’t get people lining up for that, but anyway, the mouse had no choice. We put him in a cage, and we just give him what we want. Now, here’s something I want to share with you for Greg’s amusement. He doesn’t know about this.
When he first saw my book, what does he do? He turns it over to his father to ask if I'm right! Funny, right? He suffered having to measure nail lengths as a punishment when he was a kid. So what he did to me, he punished me by giving his father my book and having him eviscerate my data.
All these red lines are Jeff Glassman’s critique. I had to sit down and spend days paging out exactly what we did, how many mice, I gave him the raw data from the experiments, and I let him look at it. I explained every one of his little red lines there and what he was concerned about. I did paraphrase—Perna said to me, my other staff member, “Boy, this is a smart guy, but we're not that dumb!”
So, we had to spend our time going back to address every one of Jeff’s criticisms. Finally, he writes me a letter, “Maybe you did more satisfactory work than I thought.” He actually accepted what I said. I got it. I got it better than you!
He actually thought you understated your case mathematically. Well, he might be right about that, but I wasn’t understating. I had to present it the way we looked at it. But it was a great experience and exercise for us to look at how someone else’s brain would view the information, and if we were able to communicate the information back and forth to satisfy both groups.
Yeah, you know, regardless of what he said, I was kind of done with it at the nuclear and mitochondrial transfer experiments. That was enough. But for a lot of people, it wasn’t. But you tell me—you’re the guy with all the answers, right? No, I don’t know either.
It’s called confirmation bias—dogma. Dogma. You can’t change religion in people. Yeah, well, I put everything out there, and people still say cancer is genetic. What are you gonna do? Anyway, we got a lot of work from Jeff’s criticisms. When you have people that are not directly in your field, and they see the data, you have to examine how they are viewing this information.
Therefore, our explanations need to be more clear and accurate to make others recognize what we’re doing. I thought you’d enjoy that because we had to spend a lot of time addressing those issues. But anyway, predictability, which is very important.
Each square is a mouse under a different dietary condition. We did linear regression analysis, which is actually choosing one as the cause and the other as the effect. So, glucose was the independent variable—beta-hydroxybutyrate is the ketone body in the blood—and the tumor weight is the size.
What we see here on the left is that as blood sugar goes down in these animals, ketones go up. This is an evolutionary conservation of energy—when you stop eating, if the brain doesn’t get energy, you’re going to go unconscious. So the body mobilizes fat, turns it into ketone bodies—water-soluble fat breakdown products.
And that’s clearly related to low insulin, higher glucagon, more ketones. But on the right, you’ll see that as the glucose goes down, the size of the tumor goes down. The tumors got smaller as the blood sugar went down. The higher the blood sugar, the faster the tumor would grow.
This is the first evidence in the scientific literature that I’m aware of, predicting that the rate of tumor growth is linked directly to blood sugar. Since this has been pointed out, we’ve seen it in glioblastoma, colon cancer, breast cancer, bladder cancer—all the different cancers that have been looked at. The higher the blood sugar, the more likely the patient will die sooner.
There is definitely a predictability in cancer for blood glucose levels. Now, what we did—based on a lot of interaction with cancer patients—is build the glucose-ketone index (GKI) calculator, which is a quantitative assessment of the ratio of glucose to ketones.
Glucose is usually measured in deciliters—we convert that to millimolar, and then we measure ketones, so you have this GKI. What we’ve determined is that levels of 2.0 or below put one in nutritional ketosis. And what is nutritional ketosis? It’s essentially the way we existed during the Paleolithic period.
We didn’t have highly processed carbohydrates in our diet—we had a lot of exercise, and almost no highly processed carbohydrates. We had to move a lot. We ate predominantly low-carbohydrate plants and animals—mostly animals. What we’re doing is simply taking people back to that.
People ask, “What do I have to eat to get a GKI?” You can do it with a ketogenic diet, a Mediterranean diet, a pescatarian diet—you can do it with any kind of diet. Each person will have to adjust for themselves, whether it’s cultural, religious, or whatever, to get their GKI. I built this for the glioblastoma patients, and then we switched it to all cancer patients.
But now, as a prevention of cancer, healthy people like these CrossFit folks and others want to see how low they can get their GKI. My good friend Dominic D'Agostino lives in this environment constantly. It’s a very good way to prevent cancer as well as manage it.
Now, what we did here was we took the concept of "press-pulse" from paleobiologists. They use it to describe the destruction of plants and animals on the planet, but we actually adopted the concepts. We have press therapies and pulse therapies.
Press therapy—you put patients on restricted ketogenic diets, water-only fasting, that kind of thing. Even ketone supplements. Stress management, like Chris was saying, is very important because when you’re under stress, glucocorticoids go up. So, you’ve got to keep your glucocorticoids down, reduce stress.
A lot of people with cancer are freaked out—they all think they’re going to die. So stress management is very important—it lowers glucose, makes the metabolic therapy work better. Then you come in with dosed timing and scheduling of glucose targeting, glutamine targeting, and hyperbaric oxygen, which can eventually replace radiation for killing tumor cells.
Hyperbaric oxygen kills tumor cells by producing ROS, but it enhances the health and vitality of the normal cells while selectively destroying the tumor cells. So we move the patient from a diseased state to a managed state, and then, with improvements in dosed timing and scheduling, we can move from management to a state of resolution.
Dr. D’Agostino is also working in my lab. We have a major paper under review right now in a major medical journal, with more than 20 MDs and PhDs, for the metabolic management of glioblastoma. This is the framework, but the nuts and bolts of how to treat cancer patients on a day-to-day basis, and all the things you might encounter in trying to treat individuals—personalized nutrition, all of these kinds of things—are in that paper.
So, when that paper comes out, there’s no excuse for anybody not to treat cancer patients because here’s the “how-to” manual to do it. Let me talk just a little bit about glioblastoma—terrible brain cancer. This is what killed John McCain, Ted Kennedy, and Bo Biden, the president’s son. It’s a terrible disease.
You can see how bad the brain looks—the patients die from intracranial pressure. Those purple cells on the right—those are the tumor cells. They go across the surface of the blood vessels, called Virchow-Robin spaces, and they seed the entire brain, even though you can’t see the tumor cells. You see only this discoloration in cystic areas, but the tumor cells are out there.
That’s why they always say, “We can never get all the cancer; it’s always there to some extent,” because the tumor cells have already seeded out into the parenchyma. Now, here’s another very interesting thing—let me just talk about predictability. Emily, didn’t you say that Greg talks about failure to replicate?
Well, nothing is more replicable than how fast you’re going to die with a GBM (glioblastoma). Look at these survival curves—this is five surgical institutions. You can’t design more replicable survival data than this. All these—and we can go all over the world to every major brain cancer center—you’re going to get a survival curve that looks like that. Highly replicable.
We just heard about how hard it is in the oncology field to replicate data—look how replicable this is. And there hasn’t been any improvement in 100 years. In 1926, the median survival was 8 to 14 months. In 2024, the median survival is 8 to 16 months. What’s going on?
We’ve got the Webb telescope for crying out loud, and we can’t move the needle on glioblastoma? Why? What is going on? Why are we not moving the needle in survivability for this cancer? We published this paper, and you ask me why people don’t listen to what we’re saying.
When you debulk the tumor—cut it out en masse—you create a wound. Then, as soon as the patient wakes up, you start irradiating them. That breaks apart the glutamine-glutamate cycle in the brain, freeing up massive amounts of glutamine—the fuel. That’s one of the two fuels!
And when you irradiate the brain, they give you high-dose steroids to reduce the inflammation, which gives you hyperglycemia. I just showed you—the higher the glucose, the faster the tumor is going to grow. It’s obvious. The two fuels driving the disregulated growth are created by the standard of care.
What we’re doing to these poor people is denying them, for the most part. You saw how replicable it is because everybody on the planet is getting the same treatment—there are no differences. Standard of care happens in India, Germany, Japan—all over the world, they’re doing the same thing.
This is explainable—it’s explainable because you're not allowing the person’s brain to recover from the surgery and targeting the glucose and the glutamine simultaneously. So we developed the therapy using the VM3 glioblastoma mouse model, which has all the growth characteristics that we see in human GBM.
And we use this drug DON—6-diazo-5-oxo-L-norleucine, which is a glutamine analog. The glutamine analog looks like glutamine and blocks glutamine utilization. So we put the mice on a ketogenic diet, lowering blood sugar and elevating ketones. I can spend hours with you, but the overall success is survival.
Survival is success. What you get is—the blue line is the untreated mice, dying fast. The green line is the diet by itself. The red line is the drug by itself. And the purple line is when you combine the diet with the drug. You can see how powerful it is.
We tried this on an Egyptian guy—he did really well at the beginning, but they insisted on irradiating him. I said to Elsaka, the attending physician, “The guy’s doing great! He’s back in the field; he’s a corn farmer, he’s a young guy!” “Oh no, we’ve got to irradiate him!” I said, “Jesus!”
Anyway, I’m here in Boston; he’s there in Alexandria, Egypt. I ask, “How’s the patient?” “He seems to be doing okay.” We published the paper. Then, at 30 months of age, he starts getting headaches. He dies at 30 months of age. When they did the autopsy, he had died from liquefaction of the brain due to radiation poisoning, not from the tumor. It was very disheartening to me.
Then I also wrote this paper, “Provocative Question,” for Harold Varmus, who runs the NCI. He had provocative questions—“change the standard of care for GBM.” Oh, can’t do that, right? Anyway, we’re not going to move the needle until we stop irradiating the brains of these poor GBM patients.
I say that in the big treatment paper as well—radiation brings huge amounts of revenue. Follow the money. Once we have this protocol, the one we’re writing is going to have a major impact if we can stop radiating these poor folks.
I always show this one—poor Brittany Maynard, remembering Brittany. She was a young woman, January 2014. Here she is with her husband, right after they got married. She gets a glioblastoma, actually from a lower-grade tumor that exploded into a GBM. She puts her story in People magazine, “I’m going to kill myself rather than take the standard of care.”
But you can see her face is swollen—that’s moon face from the high-dose steroids. When you give people high-dose steroids, they get this thing called moon face. So she dies with dignity with her family on November 1, 2014.
Now, this is our man Pablo. We wrote a case report on him. He came to us the same year as Brittany—glioblastoma, no radiation, no chemo, no steroids. He didn’t want any of that. The attending physicians told him, “You’re going to be dead, Pablo, in nine months—start getting your affairs in order.”
He said, “The hell with it!” He wanted to have kids. He said, “If I take radiation and all that stuff, I’m not going to have kids. I won’t even live to have kids.” So, he rejected that, and I’m going to talk about him in a minute. He survived with good quality of life until just this month.
But anyway, we look at his brain tumor. You can see it when it was this big thing with the arrow, then in 2016, you can see it’s bigger. He had his first debulking surgery in early 2017. It grows for another three years, and it’s cut out again. In the meantime, he gets married, he has one child, he has two children.
We found out that, in addition, he had the IDH1 mutation, which actually inhibits the glycolysis and glutaminolysis pathways, giving him a survival advantage—slight. I don’t have time to talk about that, but if anybody’s interested, I have the crew here that can go into a deep dive on that.
But the idea is, Pablo did have an advantage—he used a special diet and lifestyle together with God’s gift of a therapeutic mutation. Not all mutations are bad. Now, here’s Pablo. Thomas and I had a discussion with him in August, and we were laughing about Pablo surviving 10 years, which was... He had survived four operations on a previously inoperable tumor.
So we had a big laugh about this—“Pablo, how many more? Are you going to outlive me? Are you going to have 20 operations on your head?” We were laughing—he was perfectly healthy; there was nothing wrong with Pablo.
Then two days later, after that conversation, to our surprise, they say, “Oh, we want to go in again. There’s some residual—we think we can get it out.” So he comes out of the operating room—thumbs up, talking and everything. Then 12 hours later—cerebral hemorrhage, dead from the operation, not from the tumor.
He was our poster child for how long you can live with glioblastoma. Everybody was looking at him for hope, and everything... Poor guy. And then I know poor Danny Sheehan, from Marshfield, Massachusetts, right down here on the coast. He was diagnosed in 2017 with pineoblastoma.
It goes through the spinal cord and everything. You can see his fat face from all the steroids, radiation, everything they gave this poor little kid. Then he died in 2021 from standard of care. Now, because of that, we got a grant from a British UK Childhood Center to study childhood cancer, thankfully.
We developed the pediatric high-grade glioma model in our lab—Per, Muki, and myself—where we can put tumors into the brains of young mice, at the same age as Danny Sheehan and other little kids, and we could see the tumors going down the spinal cord. We replicated key aspects of pediatric oncology in these mice.
Now, I don’t know if I can—yeah, maybe I can get it. So, you can see the difference. The guys on the left are the ones that were not treated with metabolic therapy, and they’re all going to die—one has already died. But you can see the ones on the right—we gave them ketogenic diet, Bendamustine, and DON, targeting glucose and glutamine simultaneously while raising ketone levels, and we’re keeping these guys alive.
This is going to be a blockbuster in the pediatric clinic, but they don’t use it because cancer is a genetic disease, haven’t you heard? It’s unbelievable. This woman here was treated by Ikiki, of this clinic in Istanbul, Turkey, and you can see she was from Ohio.
She had breast cancer that spread to the brain and many other organs. All those dark spots are the spread of the breast cancer. They gave her metabolically supported chemo for managing it. They said she had one month to live—"Get your affairs in order, radiation, chemo, did all these horrible things to her." Nothing was working, so she jumped on an airplane, went to Istanbul, and almost died in the ICU for two and a half weeks, according to Abdel Slok told me.
Then they put her on this metabolically supported low-dose chemo—very low doses, we’re not throwing out anything. Like Chris said, we’re not throwing everything out—there are some things that can work if you do it the right way. Anyway, here she is celebrating her life with her husband in Hawaii in 2021.
Last week, I had to call because I know people are going to ask me, “What’s going on with the woman?” So I called up Slok. I said, “Abdel, how’s this woman doing? I don’t want to say...” “Oh no, she’s fine. She sent me a nice letter thanking me for all the wonderful life she’s had.” She was a goner, but she’s doing fine.
We got this guy from Greece—he had lung cancer that spread to the brain. Restricted ketogenic diet, primary lung cancer. Amazing guy—he’s doing fine; he’s out 10 years. I wrote a puff piece for Nature on how we can manage prostate cancer—I did all these things.
And then, of course, the dogs. Jimmy’s dog, with the big blueberry tumor on his face. This woman came to me and said, “Can you publish this, right?” So I had to drum up a veterinarian to make it look like... Lauren Nations is a friend of mine.
I said, “Lauren, come on, join us,” because I’m not a vet. In fact, the woman treated her own dog. This was a mast cell tumor on the dog’s nose. The first thing she did was say, “Okay, no more carbohydrates for you, poor dog.” It’s a pit bull.
So, what happens is that it shrinks down. She gave it raw eggs, raw chicken, fish oil, and 40% calorie restriction, just like the mice. And lo and behold, the tumor disappears. Here’s the dog in 2013 and in 2016—completely healed.
They said, “Oh, you’ve got to have radiation and chemo; it’s going to cost a lot of money, the dog will be very sick, diarrhea, all kinds of stuff.” She said, “No, I don’t want that.” So no surgery, no radiation, no chemo. Look at this—the dog died at 15 and a half years of age from heart failure.
It didn’t die from the therapy—in fact, the therapy kept the dog alive even longer. And don’t forget, I published this on autolytic cannibal autophagy, like Chris was saying, where you rearrange mitochondria and organelles within the cell. But there’s also autolytic cannibalism. When you put the body under nutritional stress, every cell in your body has to justify its existence to function as a whole.
You’ve got a tumor; those cells aren’t functioning well—eat them. So the body will turn on them and attack and eat the tumor for the good of the survival of the whole. We have stage 4 cancers—we don’t consider terminal cancer anymore. This is not right.
If you do metabolic therapy, we don’t know whether you're going to die or not. There’s this book, Cancer Revolution, by Maggie and Brad Jones. Maggie is a long-term survivor of lung cancer that spread to the brain, and she is collecting all these folks. She’s got a registry of all these people who are alive, who should have been dead, and she’s got dozens—“I’m alive! I’m alive!”—she’s got all these people that are doing various therapies.
We haven’t even standardized this yet, folks. Once we standardize this, we’re going to drop the death rate on cancer by 50% in 10 to 15 years. The problem is, how do you get through the wall of obstacles that say you can’t do this? Everything is “You can’t, you can’t, you can’t.” Remember that guy telling us, “You can’t do that.”
The hell we can’t! These people need to live, for Christ’s sake! Yes, the mitochondrial metabolic theory can explain better the origin and management of cancer than the somatic mutation theory.
When are we going to get rid of this noose on our neck with the somatic mutation crap? We can keep people alive. And yes, our conclusions—it’s not a genetic disease; it’s a mitochondrial metabolic disease, driven by substrate-level phosphorylation.
And not only that—press-pulse ketogenic therapy for chronic diseases. We’re right about this. Chronic disease—it’s all related to the lack of exercise, too much carbohydrate. Get your GKI to 2.0! Everybody should have a 2.0 GKI.
The hospitals would be running down the streets looking for somebody to treat! Everybody would be like a CrossFitter for crying out loud—they’d all be healthy. But no! You know, we have a picture in the lab. It says, "Pills and surgery," and you have a hundred obese people all lined up trying to get the pills.
Diet and lifestyle change? One guy in the line! So, you know, we’re up against a tough sell. We’re having a global society for cancer metabolic therapies. We’re collecting collaborators from all over the world.
We want to set up clinics. We have people talking to us, saying, "Okay, once the paper comes out, how are we going to set up clinics? What are we going to do? What are the nuts and bolts of this whole thing?" And, of course, we have to thank so much of our support—Greg, Broken Science, and yes, CrossFit when Greg ran it. That was definitely helpful to us.
Broken Science, the Corkin family for sure, philanthropy from Maroon and Edward Miller, Kenneth Rainin, Children with Cancer United Kingdom. Our university has been helping us tremendously. Delaware County—the deputies have been helping us. This fund is really a blessing for us.
And in the past, the National Cancer Institute and the NIH supported us. So, I thank you for your attention, and I’ll be happy to answer any questions if there are any. Thank you.