0:00 the importance of our new paper that appeared in in um ASN nuro uh last week um shows shows for the first time that um uh amino acid fermentation can also participate in the disregulated growth of the tumor cell uh and the amino acid that we're speaking predominantly about is glutamine and we tested all the other Amino all 20 amino acids we interrogated the cancer cells both Mouse and human gleo blastoma cells we interrogated them to ask which of the what fuels could they use uh to to maintain their growth so the way we do this is very simple we just take the tumor cells and we grow them in Saline salt solution a and of course there's no food there's nothing
0:46 for them to eat and then you take and time them to see how fast they die uh with no food and mouse cells because they have a very high basil metabolic rate seven times faster than that of the human they die quick when you take away their fuels Mouse cells will die in 24 hours um human human cells uh will die in about 72 hours 48 to 72 hours with no fuel just in a in what we call a buffered saline solution and then what we do is we simply add individual amino acids uh back and we see uh whether or not uh uh the viability of the cells is improved and what we see uh we do this both in the presence and absence of glucose so glucose alone will keep the cells alive longer but then they die
1:32 because they they don't have any any nitrogen Source um so and we do it without glucose so we just do it in pure nothing and then we add glucose and then we add individual amino acids back and what we see is is when we add the amino acid glutamine these cells explode in in in growth capacity uh relative to all other amino acids now we found a little bit of stimulation from glutamate uh because it's it's the it's the first product that glutamine is metabolized too uh but it's not nearly as powerful as glutamine none of the other amino acids had any come close to how powerful glutamine is so so the question is is and when you have glucose and glutamine the two Pathways the two fuels are synergistic in providing all of the metabolites and all of the energy
2:18 needed for rapid disregulated growth so the the the question is how is glutamine able to uh facilitate the growth of the tumor is it respired um uh through the respiration it's called an anotic respiratory process where the carbons of glutamine enter into the TCA cycle to produce reducing equivalence allowing oxidative phosphorilation to operate producing energy or is the glutamine fermented um which is generating energy through mitochondrial substrate level phosphorilation in the sual coal liase step within the kreb cycle or the T PCA cycle so what we what we did and why
3:03 this paper is so important is we were able to test this hypothesis many different ways so we would take all of the glucose away from the tumor in the presence of oxygen and then give glutamine and we found that the cells could survive with oxygen and glutamine in the absence of glucose but then that doesn't tell us whether the glutamine is fermented or is respired so we repeated the experiment this time remove removing all the oxygen we grew them in a deep hypoxia in the absence in the absence of glucose and we still got ATP production in these cells yes it was significantly reduced but it was still being produced ATP was still being produced in the cancer cells in the absence of oxygen
3:49 and in the absence of glucose so the question is where is that ATP coming from so we think it's coming from the substrate level phosphorilation in the T PCA cycle and we were able to show that when we use labeled glutamine c-13 glutamine we were able to see C13 succinic acid as a waste product that's the end product of the glutaminolysis pathway clearly the glutamine is coming into the cell metabolized to glutamate to alphaet glutarate to sual COA and we found labeled C13 succinate the end product of the glutaminolysis pathway meaning that the fuel is being dumped out it's not anotic to any extent it's being dumped out as a fermentation end product showing basically that um these
4:36 cells are using glutamine in a in a um non-oxidative way another experiment was we use cyanide which blocks oxidative phosphorilation and we were still able to see significant ATP in the absence of glucose and the presence of cyanide using GL glutamine as a fuel and we were still able to see this succinic acid produced clearly showing we disconnected oxygen and oxidative phosphorilation from a second major pathway in the mitochondria producing energy this is unbelievable so this is the missing part of warberg central Theory warberg had everything right most everything not everything uh he he was correct on knowing cancer was a mitochondrial metabolic disease but he did not know there was a second major fuel that these tumor cells could ferment together with glucose so this now opens up uh the
5:24 whole field of cancer to know these tumor cells are dependent on two major fermentable fuels so we're able to clear up the misunderstanding of of warberg we're also able to say that the oxygen consumed in the tumor cells is not used predominantly for ATP synthesis through oxidative phosphorilation another mistake that warberg and almost everyone else in the field makes they think that the uh consume oxygen consumption rate is being used for oxidative phosphorilation we have clearly shown that this cannot be the case the cells are taking in oxygen yes but they're not using it for ATP production through oxidative phosphorilation it's the fermentation metabolism in the mitochondria itself and in the cytoplasm through substrate level phosphorilation this is the new thing this will lead to the to the eventual management of cancer
6:10 because we now know how to we now know how to kill the Beast without toxicity these were inv vitro experiments done in because we need to farad out mechanisms of how cells are surviving in Vivo we bring them into the culture dish now people will say oh well that's all in the culture you have no clue we grow when we grow these gasto cells in the mouse and we simultaneously Target glucose and glutamine using drugs and diet we get a very powerful uh very powerful effect shutting down uh the glucose and glutamine Pathways extremely powerful with minimal of any toxicity this this is the reason we we the mechanism is shown in vitro and the outcome in Vivo is clear based on the mechanisms the hypothesis cancer is a mitochondrial metabolic disease driven
6:56 by a fermentation metabolism the fermentation is happening in the mitochondria and it's happening in the cytoplasm so if we know that then we design an experiment in Vivo and show that if I Target glucose and glutamine while transitioning the body to nutritional ketosis I get massive reduction of the tumor without toxicity reducing inflammation uh and acidification reducing all of the different characteristics that you see and killing tumor cells Mass killing of these tumor cells so clearly this is what's going to happen this is just the beginning we're going to perfect this system so that we can use it in all clinical studies of cancer should be targeting glucose and glutamine while the patient is in nutritional ketosis because the science tells us that's what we should do the cancer cells are telling us this is what we should do the
7:41 cancer cells themselves are siging us and saying I am fermenting here is the evidence that I am fermenting this is keeping my energy and my growth capabilities and we we're looking at that and saying okay well if I take away your energy you should die and that's exactly what happens not complicated how did you know prior to this that glutamine was being fermented I didn't we didn't know we knew glutamine was a powerful fuel for cancer but we didn't know if it was fermented or not I I proposed that in my book originally I said that I think glutamine is being used speculation I speculated for the first time that I think glutamine is a fermentable fuel ba based on the findings of hokka years ago hokka did a very interesting experiment he took animals and he had them diving
8:27 uh animals that normally dive on water like seals um and porpuses and these kinds of animals and he put them underwater for periods of time and then looked at the metabolites in the bloodstream and the first thing he saw was a massive increase in lactic acid and succinic acid and he speculated that the suconic acid was there because of some sort of amino acid fermentation but he never knew what the amino acid was or what was going on he didn't know how it was being fermented so I looked at his work and I said I think it's being ferment mented in the mitochondria uh which was which was kind of uh novel at the time uh and I said well I speculate this what it was then I work with my good friend uh Christo chinopoulos from semil Weiss University in Budapest who's
9:13 the world leader on mitochondrial substrate level phosphorilation I ran my idea by him he looked at it he says yeah maybe uh the way I set it up in my book was not accurate but the concept could be very viable so then we started a a seven year uh plan on looking at mitochondrial substrate Level phosphorilation under different conditions and this paper is the culmination of all of the research that we did proving that mitochondrial substrate level phosphorilation is a major source of ATP and energy driving the disregulated growth of these brain tumors this is why when you go in Vivo now you can manage cancer by by taking away the two fermentable fuels and we plan to do if we can get funding we plan to go through all the major cancers lung cancer colon cancer ladder cancer breast
10:00 cancer because they're all show lactic acid and suic acid as as waste products all of these cancers are telling us the same thing we are fermenting you want to kill us you got to take away the fermentable fuels the cancer cells have been telling us this for decades since the time of warberg but just nobody it hasn't fall on the on the ear because everybody thinks it's being driven by genetic mutations the mutations are an effects of all this process they're not the drivers they're the effects we want to stop the growth we want to prevent acidification we want to clean up the micro environment you got to take away the two fermentable fuels and they can't burn fatty acids or ketones and people say oh they can switch they're Flex they're not flexible we have already shown they're not flexible they're restricted to a fermentation metabolism so all this nonsense about they can burn
10:46 fatty acids they can't I have the paper showing they can't do this nobody has shown cancer cells growing in the absence of glucose and glutamine on any other fuel besides glucose and glutamine so so um so this is where it is it's just a matter of time I don't know how long it's going to take the field to understand what I'm saying but once they understand what I'm saying the death rates of cancer are going to be dropping very significantly so your speculation about glutamine being the other fermentable fuel in cancer cells turned out to be correct what did you learn though about this seven years what did you learn from this seven years well you have to design experiments that give you clear clear answers to support or not support your hypothesis so the hypothesis is these cell yeah every body knows glutamine a lot of people call glutamine
11:32 addicted cancer cells are glutamine addicted but if you read the papers they're saying glutamine is respired in a functional mitochondria using oxidative phosphorilation that's wrong that's not right we don't rule it out completely but it's not by itself uh necessary or sufficient to drive the disregulated growth the fermentation metabolism is the Big Driver of this problem yes you can get a little energy through oxidative F but most of that oxygen coming into the cancer cell is not being used for ATP synthesis it's being used for other things so the driver of this whole process is the fermentation of glutamine and the fermentation uh mechanism of of glucose throwing out lactic acid and succinic acid acidifying the micro environment cancer cells are telling us exactly uh
12:19 what's wrong with them and they're telling us exactly how to manage them
